Phosphatidylinositol 3-kinase (PI3K) is a family of lipid kinases that phosphorylate phosphatidylinositol at the 3′ position of the inositol ring. PI3K is comprised of several classes of genes, including Class IA, IB, II and III and some of these classes contain several isoforms (reviewed in Engelman et al., Nature Review Genetics 7:606-619 (2006)). Adding to the complexity of this family is the fact that PI3Ks function as heterodimers, comprising a catalytic domain and a regulatory domain. The PI3K family is structurally related to a larger group of lipid and serine/threonine protein kinases known as the phosphatidylinositol 3-kinase like kinases (PIKKs), which also includes DNA-PK, ATM, ATR, mTOR, TRRAP and SMG1.
PI3K is activated downstream of various mitogenic signals mediated through receptor tyrosine kinases, and subsequently stimulates a variety of biological outcomes; including increased cell survival, cell cycle progression, cell growth, cell metabolism, cell migration and angiogenesis (reviewed in Cantley, Science 296:1655-57 (2002); Hennessy et al., Nature Reviews Drug Discovery 4:988-1004 (2005); Engelman et al., Nature Review Genetics 7:606-619 (2006)). Thus, PI3K hyper-activation is associated with a number of hyper-proliferative, inflammatory, or cardiovascular disorders; including cancer, inflammation, and cardiovascular disease.
There are a number of genetic aberrations that lead to constitutive PI3K signaling; including activating mutations in PI3K itself (Hennessy et al., Nature Reviews Drug Discovery 4:988-1004 (2005); reviewed in Bader et al., Nature Reviews Cancer 5:921-9 (2005)); RAS (reviewed in Downward Nature Reviews Cancer 3:11-22 (2003)) and upstream receptor tyrosine kinases (reviewed in Zwick et al., Trends in Molecular Medicine 8:17-23 (2002)) as well as inactivating mutations in the tumor suppressor PTEN (reviewed in Cully et al., Nature Reviews Cancer 6:184-92 (2006)). Mutations in each of these gene classes have proven to be oncogenic and are commonly found in a variety of cancers.
The molecules defined within this invention inhibit the activity of PI3K, and therefore may be useful for the treatment of proliferative, inflammatory, or cardiovascular disorders. Cases where PI3K pathway mutations have been linked to proliferative disorders where the molecules defined within this invention may have a therapeutic benefit include benign and malignant tumors and cancers from diverse lineage, including but not limited to those derived from colon (Samuels et al., Science 304:554 (2004); reviewed in Karakas et al., British Journal of Cancer 94: 455-59 (2006)), liver (reviewed in Karakas et al., British Journal of Cancer 94: 455-59 (2006)), intestine (reviewed in Hennessy et al., Nature Reviews Drug Discovery 4:988-1004 (2005)), stomach (Samuels et al., Science 304:554 (2004); reviewed in Karakas et al., British Journal of Cancer 94: 455-59 (2006)), esophagus (Phillips et al., International Journal of Cancer 118:2644-6 (2006)); pancreas (reviewed in Downward Nature Reviews Cancer 3:11-22 (2003)); skin (reviewed in Hennessy et al., Nature Reviews Drug Discovery 4:988-1004 (2005)), prostate (reviewed in Hennessy et al., Nature Reviews Drug Discovery 4:988-1004 (2005)), lung (Samuels et al., Science 304:554 (2004); reviewed in Karakas et al., British Journal of Cancer 94: 455-59 (2006)), breast (Samuels et al., Science 304:554 (2004); Isakoff et al., Can Res 65:10992-1000 (2005); reviewed in Karakas et al., British Journal of Cancer 94: 455-59 (2006)), endometrium (Oda et al., Can Res 65:10669-73 (2005); reviewed in Hennessy et al., Nature Reviews Drug Discovery 4:988-1004 (2005)), cervix (reviewed in Hennessy et al., Nature Reviews Drug Discovery 4:988-1004 (2005)); ovary (Shayesteh et al., Nature Genetics 21:99-102 (1999); reviewed in Karakas et al., British Journal of Cancer 94: 455-59 (2006)), testes (Moul et al., Genes Chromosomes Cancer 5:109-18 (1992); Di Vizio et al., Oncogene 24:1882-94 (2005)), hematological cells (reviewed in Karakas et al., British Journal of Cancer 94: 455-59 (2006); Hennessy et al., Nature Reviews Drug Discovery 4:988-1004 (2005)), pancreas (reviewed in Downward Nature Reviews Cancer 3:11-22 (2003)), thyroid (reviewed in Downward Nature Reviews Cancer 3:11-22 (2003); reviewed in Hennessy et al., Nature Reviews Drug Discovery 4:988-1004 (2005)); brain (Samuels et al., Science 304:554 (2004); reviewed in Karakas et al., British Journal of Cancer 94: 455-59 (2006)), bladder (Lopez-Knowles et al., Cancer Research 66:7401-7404 (2006); Hennessy et al., Nature Reviews Drug Discovery 4:988-1004 (2005)); kidney (reviewed in Downward Nature Reviews Cancer 3:11-22 (2003)) and Head and Neck (reviewed in Engelman et al., Nature Reviews Genetics 7:606-619 (2006)).
Other classes of disorders with aberrant PI3K pathway signaling where the molecules defined within this invention may have a therapeutic benefit include inflammatory and cardiovascular diseases, including but not limited to allergies/anaphylaxis (reviewed in Rommel et al., Nature Reviews Immunology 7:191-201 (2007)), acute and chronic inflammation (reviewed in Ruckle et al., Nature Reviews Drug Discovery 5:903-12 (2006); reviewed in Rommel et al., Nature Reviews Immunology 7:191-201 (2007)), rheumatoid arthritis (reviewed in Rommel et al., Nature Reviews Immunology 7:191-201 (2007)); autoimmunity disorders (reviewed in Ruckle et al., Nature Reviews Drug Discovery 5:903-12 (2006)), thrombosis (Jackson et al., Nature Medicine 11:507-14 (2005); reviewed in Ruckle et al., Nature Reviews Drug Discovery 5:903-12 (2006)), hypertension (reviewed in Ruckle et al., Nature Reviews Drug Discovery 5:903-12 (2006)), cardiac hypertrophy (reviewed in Proud et al., Cardiovascular Research 63:403-13 (2004)), and heart failure (reviewed in Mocanu et al., British Journal of Pharmacology 150:833-8 (2007)).
Clearly, it would be beneficial to provide novel PI3K inhibitors that possess good therapeutic properties, especially for the treatment of proliferative, inflammatory, or cardiovascular disorders.
1. General Description of Compounds of the Invention:
This invention provides compounds that are inhibitors of PI3K and/or mTOR, and accordingly are useful for the treatment of proliferative, inflammatory, or cardiovascular disorders. The compounds of this invention are [1] represented by formula I-A and I-B:
or a pharmaceutically acceptable salt thereof, wherein:                G1 is N or CR3, wherein R3 is H, —CN, halogen, —Z—R5, C1-6 aliphatic, or 3-10-membered cycloaliphatic, wherein:                    Z is selected from an optionally substituted C1-3 alkylene chain, —O—, —N(R3a)—, —S—, —S(O)—, —S(O)2—, —C(O)—, —CO2—, —C(O)NR3a—, —N(R3a)C(O)—, —N(R3a)CO2—, —S(O)2NR3a—, —N(R3a)S(O)2—, —OC(O)N(R3a)—, —N(R3a)C(O)NR3a—, —N(R3a)S(O)2N(R3a)—, or —OC(O)—;            R3a is hydrogen or an optionally substituted C1-4 aliphatic, and            R5 is an optionally substituted group selected from C1-6 aliphatic, 3-10-membered cycloaliphatic, 4-10-membered heterocyclyl having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur, 6-10-membered aryl, or 5-10-membered heteroaryl having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur;                        R1 is CY, —CON(R4)2, —NHCOR4, —NHSO2R4, —NHCON(R4)2, —NHCOOR4, —NHSO2N(R4)2, or —NHSO2OR4, wherein:                    CY is                        
                                     wherein:            X1, X2, and X3, are each independently N, O, S, or CR7, provided that only one of X1, X2, or X3 may be O or S,            G2 is —N═ or —NR4′—, wherein:            each occurrence of R4 and R4′ is independently H, —Z2—R6, optionally substituted C1-6 aliphatic, or optionally substituted 3-10-membered cycloaliphatic, wherein:                            Z2 is selected from an optionally substituted C1-3 alkylene chain, —S(O)—, —S(O)2—, —C(O)—, —CO2—, —C(O)NR4a—, or —S(O)2NR4a—.                R4a is hydrogen or an optionally substituted C1-4 aliphatic, and                R6 is an optionally substituted group selected from C1-6 aliphatic, 3-10-membered cycloaliphatic, 4-10-membered heterocyclyl having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur, 6-10-membered aryl, or 5-10-membered heteroaryl having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur;                                    each occurrence of R4a is independently hydrogen, —CN, halogen, —Z3—R8, C1-6 aliphatic, or 3-10-membered cycloaliphatic, wherein:                            Z3 is selected from an optionally substituted C1-3 alkylene chain, —O—, —N(R7a)—, —S—, —S(O)—, —S(O)2—, —C(O)—, —CO2—, —C(O)NR7a—, —N(R7a)C(O)—, —N(R7a)CO2—, —S(O)2NR7a—, —N(R7a)S(O)2—, —OC(O)N(R7a)—, —N(R7a)C(O)NR7a—, —N(R7a)S(O)2N(R7a)—, or —OC(O)—.                R7a is hydrogen or an optionally substituted C1-4 aliphatic, and                R8 is an optionally substituted group selected from C1-6 aliphatic, 3-10-membered cycloaliphatic, 4-10-membered heterocyclyl having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur, 6-10-membered aryl, or 5-10-membered heteroaryl having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur,                                    R2 is halogen, —W—R9, or —R9, wherein:                            W is selected from an optionally substituted C1-3 alkylene chain, —O—, —N(R2a)—, —S—, —S(O)—, —S(O)2—, —C(O)—, —CO2—, —C(O)NR2a—, —N(R2a)C(O)—, —N(R2a)CO2—, —S(O)2NR2a—, —N(R2a)S(O)2—, —OC(O)N(R2a)—, —N(R2a)C(O)NR2a—, —N(R2a)S(O)2N(R2a)—, or —OC(O)—.                R2a is hydrogen or an optionally substituted C1-4 aliphatic, and                                    R9 is an optionally substituted group selected from C1-6 aliphatic, 3-10-membered cycloaliphatic, 4-10-membered heterocyclyl having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur, 6-10-membered aryl, or 5-10-membered heteroaryl having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur; and                        HY is an optionally substituted nitrogen-containing heteroaryl group, provided that the optionally substituted nitrogen-containing heteroaryl group is a group other than a 3-isoxazolyl, a 2-pyridyl, a 3-pyridyl, a 5-pyrimidinyl, a 2-pyrimidinyl, a 5,6-dimethoxy-1H-benzimidazole group, or a pyrazinyl group,        provided that:        i) for compounds of formula I-A, the compound is other than those compounds where:        G1 is CR3; R1 is —CONHR4, or        
                 where X1, X2, and X3 are each independently N or CR7; and HY is an optionally substituted 6-membered nitrogen-containing heteroaryl group;        ii) for compounds of formula I-A or I-B, the compound is other than those compounds where:        G1 is N; R1 is        
                 or CON(R4)2; and HY is an optionally substituted nitrogen-containing aromatic heterocyclic group;        and further provided that:        iii) for compounds of formula I-A when R1 is —CON(R4)2, then R2 is an optionally substituted group selected from 6-10-membered aryl, or 5-10-membered heteroaryl having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur, provided that compounds are other than: 2-thiophenecarboxamide, 5-dibenz[b,f][1,4]oxazepin-11-yl-N-hydroxy-3-phenyl-; 5-Thiazolecarboxamide, 2-(3,4-dihydro-1(2H)-quinolinyl)-N-hydroxy-4-phenyl-; 5-Thiazolecarboxamide, N-hydroxy-4-phenyl-2-(4-pyridinyl)-; 5-Thiazolecarboxamide, N-[2′-(aminosulfonyl)[1,1′-biphenyl]-2-yl]-4-(4-methoxyphenyl)-2-(1H-pyrrol-1-yl)-; 5-Thiazolecarboxamide, 4-(4-nitrophenyl)-2-(4-pyridinyl)-N-(3-trifluoromethyl)phenyl]-; 5-Thiazolecarboxamide, 4-(4-bromophenyl)-N-(1-methylethyl)-2-(2-propyl-4-pyridinyl)-; 5-Thiazolecarboxamide, 2-(2,3-dihydro-1H-indol-1-yl)-4-phenyl-N-(phenylmethyl)-; 5-Thiazolecarboxamide, 2-(2,3-dihydro-4H-1,4-benzoxazin-4-yl)-4-phenyl-N-(phenylmethyl)-; 5-Thiazolecarboxamide, 4-phenyl-N-[(1S,2S)-2-(phenylmethoxy)cyclopentyl]-2-(1H-pyrazol-1-yl)-; 5-Thiazolecarboxamide, 4-phenyl-N-(phenylmethyl)-2-(1H-pyrazol-1-yl)-; 5-Thiazolecarboxamide, N-[(4-chlorophenyl)methyl]-2-(3-methoxy-1H-pyrazol-1-yl)-4-phenyl-; 5-Thiazolecarboxamide, 4-phenyl-N-[1-(phenylmethyl)-3-pyrrolidinyl]-2-(1H-pyrazol-1-yl)-; 5-Thiazolecarboxamide, 2-(1H-benzimidazol-1-yl)-4-phenyl-; 5-Thiazolecarboxamide, N-[(1S,2R)-1-[(3,5-difluorophenyl)methyl]-3-[1-(3-ethynylphenyl)cyclopropyl]amino]-2-hydroxypropyl]-4-phenyl-2-(1H-pyrrol-1-yl)-; 4-Thiazolecarboxamide, 2-(4-acetyl)-5-methyl-1H-1,2,3-triazol-1-yl)-N,N-diethyl-5-phenyl-; 3-Thiophenecarboxamide, N-[1-(aminoethyl)-2-phenylethyl]-2-(3-furanyl)-5-(1-methyl-1H-pyrazol-5-yl)-, hydrochloride; 3-Thiophenecarboxamide, N-[1-(aminoethyl)-2-phenylethyl]-2-(3-furanyl)-5-(1-methyl-1H-pyrazol-5-yl)-; Carbamic acid, N-[2-[[[2-(3-furanyl)-5-(1-methyl-1H-pyrazol-5-yl)-3-thienyl]carbonyl]amino-3-phenylpropyl]-, 1,1-dimethylethylester; 3-Thiophenecarboxamide, N-methyl,2,5-di-4-pyridinyl-; 3-Thiophenecarboxamide, 2,5-di-4-pyridinyl-; 1H-1,2,3-triazole-4-acetic acid, 1-[4-[(diethylamino)carbonyl]-5-phenyl-2-thiazolyl]-5-methyl-a-oxo-, ethyl ester; 4-Thiazolecarboxamide, 2-[4-(1,2-dioxopropyl)-5-methyl-1H-1,2,3-triazol-1-yl]-N,N-diethyl-5-phenyl-; and for compounds of formula I-B, when G1 is N, R2 is substituted or unsubstituted phenyl or pyridyl, and HY is substituted or unsubstituted 1H-indazol-3-yl, then R1 is other than CON(R4)2;                    for compounds for formula I-A or I-B compounds are other than: 3-thiophenecarboxylic acid-2-(acetylamino)-5-[7-(4-chlorophenyl)-1,7-dihydro-2-(trifluoromethyl) [1,2,4]triazolo[1,5-a]pyrimidin-5-yl]-4-methyl-ethyl ester; 3-thiophenecarboxylic acid-2-(acetylamino)-5-[7-(4-chlorophenyl)-1,7-dihydro-2-(trifluoromethyl) [1,2,4]triazolo[1,5-a]pyrimidin-5-yl]-4-methyl-, ethyl ester; 5-Thiazoleacetamide, N-[[(2S)-4-[(3,4-difluorophenyl)methyl]-2-morpholinyl]methyl]-4-methyl-2-(5-methyl-3-isoxazolyl)-; 5-Thiazoleacetamide, N-[[(2S)-4-[(3,4-dichlorophenyl)methyl]-2-morpholinyl]methyl]-4-methyl-2-(5-methyl-3-isoxazolyl)-; Benzenecarboximidamide, 4-chloro-N-[[[[4-methyl-2-(2-thienyl)-5-thiazolyl]amino]carbonyl]oxy]-; Benzenecarboximidamide, N-[[[[4-methyl-2-(2-thienyl)-5-thiazolyl]amino]carbonyl]oxy]-4-(trifluoromethyl)-; Benzenecarboximidamide, 4-(1,1-dimethylethyl)-N-[[[[4-methyl-2-(2-thienyl)-5-thiazolyl]amino]carbonyl]oxy]-; Urea, N-(4-chlorophenyl)-N′-[4-methyl-2-(2-thienyl)-5-thiazolyl]-; or Urea, N-[4-(1-methylethyl)phenyl]-N′-[4-methyl-2-(2-thienyl)-5-thiazolyl]-;                        iv) for compounds of formula I-A or I-B:                    a) when R1 is NHCO(R4)2, G1 is CR3, and R2 or R3 is Br, then HY is other than an optionally substituted 1H-pyrrolo[2,3-b]pyridin-4-yl group;            b) when G1 is CR3, R1 is —NHCOR4, and R2 or R3 is CONH2, then HY is other than an optionally substituted 4,5,6,7-tetrahydro-1H-indol-1-yl or 4,5,6,7-tetrahydro-1H-indazol-1-yl group;            c) when R1 is NHCOR4, G1 is CR3, and R2 or R3 is Me, then HY is other than an optionally substituted group selected from:                        
                                     wherein ring A is an optionally substituted fused thiadiazin-3-yl, thiadiazol-3-yl, or benzo group;            d) compounds are other than those compounds where R1 or R2 is Br, R1 is —NHCOR4, and HY is optionally substituted 1H-pyrrolo[2,3-b]pyridine-4-yl;            e) compounds are other than 1H-Benzimidazole, 2,2′-[benzo[1,2-b:5,4-b′]dithiophene-2,6-diylbis(4-hexyl-5,2-thiophenediyl)]bis-; Imidazo[1,2-b]pyridazine, 8-(1-ethylpropyl)-2,6-dimethyl-3-[3-methyl-5-(2H-tetrazol-5-yl)-2-thienyl];            f) compounds are other than those compounds where R1 is —NHCON(R4)2, —NHCOR4, or NHCOOR4, and R2 is —CN, —COOR9, OR9, or —CONR2aR9;            g) compounds are other than: Acetamide, N-[5-(1H-benzotriazol-1-yl)-3-cyano-4-methyl-2-thienyl]-            h) compounds are other than: 2-Butenoic acid, 4-[[4-amino-5-(2-benzothiazolyl)-3-cyano-2-thienyl]amino]-4-oxo-; or 3-Thiophenecarboxylic acid, 4-amino-5-(2-benzothiazolyl)-2-[(3-carboxy-1-oxo-2-propen-1-yl)amino]-, 3-ethyl ester; 2-Butenoic acid, 4-[[4-amino-5-(2-benzothiazolyl)-3-cyano-2-thienyl]amino]-4-oxo-; 3-Thiophenecarboxylic acid, 4-amino-5-(2-benzothiazolyl)-2-[(3-carboxy-1-oxo-2-propen-1-yl)amino]-, 3-ethyl ester            i) compounds are other than: -Benzimidazole, 2,2′-(3,4-dimethyl-2,5-thiophenediyl)bis[5-butoxy-4,6-dichloro-; 1H-Benzimidazole-6-carbonitrile, 2-[5-(6-dodecyl-1H-benzimidazol-2-yl)-3,4-diethoxy-2-thienyl]-; or 1H-Benzimidazole, 2,2′-[3,4-bis(phenylmethyl)-2,5-thiophenediyl]bis[5-(phenylmethyl)-            j) compounds are other than 7H-Pyrrolo[2,3-d]pyrimidin-2-amine, 4-[4-methyl-5-(2H-tetrazol-5-yl)-2-thienyl]-N-[4-[2-(1-pyrrolidinyl)ethoxy]phenyl]-            k) compounds are other than: Thiophene, 2,5-bis(2-benzimidazolyl)-3,4-dibromo-;            l) compounds are other than: Tricyclo[3.3.1.13,7]decane-1-carboxamide, N-[3-[2-(dimethylamino)-1-hydroxyethyl]-5-(8-quinolinyl)-2-thienyl]-; or Tricyclo[3.3.1.13,7]decane-1-carboxamide, N-[3-[2-(dimethylamino)acetyl]-5-(8-quinolinyl)-2-thienyl]-; and            m) compounds are other than Thiophene, 2,5-bis(2-benzimidazolyl)-3,4-dibromo-;            n) compounds are other than: Acetemide, N-[5-(4-acetyl-5-[4-[(2,4-dichlorophenyl)methoxy]-3-methoxyphenyl]-4,5-dihydro-1,3,4-oxadiazol-2-yl]-3-cyano-4-methyl-2-thienyl]-; Butanamide, N-[3-cyano-5-[3-[(2,4-dichlorophenyl)methyl]-1,2,4-oxadiazol-5-yl]-4-methyl-2-thienyl]-2-ethyl-; Acetamide, 2-bromo-N-[3-(2-chlorobenzoyl)-5-(4,5-dihydro-4,4-dimethyl-2-oxazolyl)-2-thienyl; and Acetamide, 2-amino-N-[3-(2-chlorobenzoyl)-5-(4,5-dihydro-4,4-dimethyl-2-oxazolyl)-2-thienyl]-                        
The invention also provides [2] compounds of [1] wherein R1 is CY, and CY is

The invention also provides [3], compounds of [1] wherein R1 is —CON(R4)2, —NHCOR4, —NHSO2R4, —NHCON(R4)2, —NHCOOR4, —NHSO2N(R4)2, or —NHSO2OR4.
Also provided is [4], compounds of [1] or [2], wherein HY is selected from:

wherein R10 is —R10b, —V1—R10c, -T1-R10b, or —V1-T1-R10b wherein:                V1 is —NR10a—, —NR10a—C(S)—, —NR10a—C(NR10a)—, NR10aC(O)OR10a—, NR10aC(O)NR10a—, NR1aC(O)SR10a—, NR1aC(S)OR10a—, NR10aC(S)NR10a—, NR10aC(S)SR10a—, —NR10aC(NR10a)OR10a—, —NR10aC(NR10a)NR10a—, —NR10aS(O)2—, —NR10aS(O)2NR10a—, —C(O)—, —CO2—, —C(O)NR10a—, C(O)NR10aO—, —SO2—, or —SO2NR10a—;        each occurrence of R10a is independently hydrogen or an optionally substituted group selected from C1-6aliphatic, 3-10-membered cycloaliphatic, 4-10-membered heterocyclyl having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur, 6-10-membered aryl, or 5-10-membered heteroaryl having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur;        T1 is an optionally substituted C1-C6 alkylene chain wherein the alkylene chain optionally is interrupted by —N(R10a)—, —O—, —S—, —S(O)—, —S(O)2—, —C(O)—, —C(O)O—, —C(O)N(R10a)—, —S(O)2N(R10a)—, —OC(O)N(R10a)—, —N(R10a)C(O)—, —N(R10a)SO2—, —N(R10a)C(O)O—, —NR10aC(O)N(R10a)—, —N(R10a)S(O)2N(R10a)—, —OC(O)—, or —C(O)N(R10a)—O— or wherein T1 forms part of an optionally substituted 3-7 membered cycloaliphatic or heterocyclyl ring;        each occurrence of R10b is independently hydrogen, halogen, —CN, —NO2, —N(R10a)2, —OR10a, —SR10a, —S(O)2R10a, —C(O)R10a, —C(O)OR10a, —C(O)N(R10a)2, —S(O)2N(R10a)2, —OC(O)N(R10a)2, —N(R10a)C(O)R10a, —N(R10a)SO2R10a, —N(R10a)C(O)OR10a, —N(R10a)C(O)N(R10a)2, or —N(R10a)SO2N(R10a)2, or an optionally substituted group selected from 3-10-membered cycloaliphatic, 4-10-membered heterocyclyl having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur, 6-10-membered aryl, or 5-10-membered heteroaryl having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur;        each occurrence of R10c is independently hydrogen or an optionally substituted group selected from C1-6 aliphatic, 3-10-membered cycloaliphatic, 4-10-membered heterocyclyl having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur, 6-10-membered aryl, or 5-10-membered heteroaryl having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or        R10a and R10c taken together with a nitrogen atom to which they are bound form an optionally substituted 4-7-membered heterocyclyl ring having 0-1 additional heteroatoms independently selected from nitrogen, oxygen, or sulfur,                    wherein each occurrence of X4, X5, and X6 is independently N or CR10,            or two adjacent groups selected from Y, R11, R10, X4, X5, and X6, taken together, form an optionally substituted group selected from 3-10-membered cycloaliphatic, 4-10-membered heterocyclyl having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur, 6-10-membered aryl, or 5-10-membered heteroaryl having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur, and            each occurrence of R11 is independently hydrogen, —C(O)R11a—, —CO2R11a—, —C(O)NR11a—, C(O)NR11aO—, —SO2R11a—, —SO2NR11a—, or an optionally substituted group selected from C1-6aliphatic, 3-10-membered cycloaliphatic, 4-10-membered heterocyclyl having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur, 6-10-membered aryl, or 5-10-membered heteroaryl having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur;            wherein each occurrence of R11a is independently hydrogen or an optionally substituted group selected from C1-6aliphatic, 3-10-membered cycloaliphatic, 4-10-membered heterocyclyl having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur, 6-10-membered aryl, or 5-10-membered heteroaryl having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur; and                        Y is N or CR10.        
The invention also provides [5] compounds of [4], wherein HY is selected from:
                wherein each HY group is optionally additionally substituted with one or more occurrences of R10.        
The invention also provides [6] compounds of [5], wherein HY is selected from:
                wherein each HY group is optionally additionally substituted with one or more occurrences of R10.        
The invention also provides [7] compounds of [5], wherein HY is selected from:
                wherein each HY group is optionally additionally substituted with one or more occurrences of R10.        
The invention also provides [8] compounds of [7], wherein HY is selected from:
                wherein each HY group is optionally additionally substituted with one or more occurrences of R10.        
The invention also provides [9] compounds of [1] or [2], wherein HY is selected from:
                wherein each HY group is optionally additionally substituted with one or more occurrences of R10.        
The invention also provides [10] compounds of [9], wherein HY is selected from:

The invention also provides [11] compounds of [1] or [2], wherein G1 is CR3.
The invention also provides [12] compounds of [11], wherein G1 is CH.
The invention also provides [13] compounds of [1] or [2], wherein G1 is N.
The invention also provides [14] compounds of [1] or [2], wherein R2 is a 3-10-membered cycloaliphatic, 4-10-membered heterocyclyl having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur 6-10-membered aryl, or 5-10-membered heteroaryl having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur, optionally substituted with 1-4 independent occurrences of R12, wherein R12 is —R12a, -T2-R12d, or —V2-T2-R12d, and:                each occurrence of R9a is independently halogen, —CN, —NO2, —R12c, —N(R12b)2, OR12b, —SR12c, —S(O)2R12c, —C(O)R12b, —C(O)OR12b, —C(O)N(R12b)2, —S(O)2N(R12b)2, —OC(O)N(R12b)2, —N(R12e)C(O)R12b, —N(R12e)SO2R12c, —N(R12e)C(O)OR12b, —N(R12e)C(O)N(R12b)2, or —N(R12e)SO2N(R12b)2, or two occurrences of R12b, taken together with a nitrogen atom to which they are bound, form an optionally substituted 4-7-membered heterocyclyl ring having 0-1 additional heteroatoms selected from nitrogen, oxygen, or sulfur;                    each occurrence of R12b is independently hydrogen or an optionally substituted group selected from C1-C6 aliphatic, 3-10-membered cycloaliphatic, 4-10-membered heterocyclyl having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur, 6-10-membered aryl, or 5-10-membered heteroaryl having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur;            each occurrence of R12c is independently an optionally substituted group selected from C1-C6 aliphatic, 3-10-membered cycloaliphatic, 4-10-membered heterocyclyl having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur, 6-10-membered aryl, or 5-10-membered heteroaryl having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur;            each occurrence of R12d is independently hydrogen or an optionally substituted from 3-10-membered cycloaliphatic, 4-10-membered heterocyclyl having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur, 6-10-membered aryl, or 5-10-membered heteroaryl having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur;            each occurrence of R12e is independently hydrogen or an optionally substituted C1-6 aliphatic group;            each occurrence of V2 is independently —N(R12e)—, —O—, —S—, —S(O)—, —S(O)2—, —C(O)—, —C(O)O—, —C(O)N(R12e)—, —S(O)2N(R12e)—, —OC(O)N(R12e)—, —N(R12e)C(O)—, —N(R12e)SO2—, —N(R12e)C(O)O—, —NR12eC(O)N(R12e)—, —N(R)SO2N(R12e)—, —OC(O)—, or —C(O)N(R12e)—O—; and            T2 is an optionally substituted C1-C6 alkylene chain wherein the alkylene chain optionally is interrupted by —N(R13)—, —O—, —S—, —S(O)—, —S(O)2—, —C(O)—, —C(O)O—, —C(O)N(R13)—, —S(O)2N(R13)—, —OC(O)N(R13)—, —N(R13)C(O)—, —N(R13)SO2—, —N(R13)C(O)O—, —NR13C(O)N(R13)—, —N(R13)S(O)2N(R13)—, —OC(O)—, or —C(O)N(R13)—O— or wherein T3 or a portion thereof optionally forms part of an optionally substituted 3-7 membered cycloaliphatic or heterocyclyl ring, wherein R13 is hydrogen or an optionally substituted C1-4aliphatic group.                        
The invention also provides [15] compounds of [14] wherein R2 is an optionally substituted 6-10-membered aryl or 5-10-membered heteroaryl having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur.
The invention also provides [16] compounds of [15] wherein R2 is a phenyl group substituted with 1-3 independent occurrences of halogen, C1-3 alkyl, CN, C1-3haloalkyl, —OC1-3 alkyl, —OC1-3 haloalkyl, —NHC(O)C1-3 alkyl, —NHC(O)NHC1-3 alkyl, NHS(O)2C1-3 alkyl, or —C(O)H.
The invention also provides [17], compounds of [16] wherein R2 is halogen.
The invention also provides [18], compounds of [1] or [2] wherein when R1 is CY, X1 is N, G2 is NR4′, and X2 and X3 are CR7.
The invention also provides [19], compounds of [18], wherein X3 is CH.
The invention also provides [20], compounds of [1] or [2], wherein when R1 is CY, X1 and X2 are N, O2 is NR4′ and X3 is CR7.
The invention also provides [21], compounds of [20] wherein R7 is H or NH2.
The invention also provides [22], compounds of [1], wherein one or more, or all, of R1, R2 and HY are selected from:                a. R1 is CY, and CY is        
                b. R2 is a 3-10-membered cycloaliphatic, 4-10-membered heterocyclyl having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur 6-10-membered aryl, or 5-10-membered heteroaryl having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur, optionally substituted with 1-4 independent occurrences of R12, wherein R12 is —R12a, -T2-R12d, or —V2-T2-R12d, and:                    each occurrence of R9a is independently halogen, —CN, —NO2, —R12c, —N(R12b)2, —OR12b, —SR12c, —S(O)2R12c, —C(O)R12b, —C(O)OR12c, —C(O)N(R12)2, —S(O)2N(R12b)2, —OC(O)N(R12b)2, —N(R12e)C(O)R12b, —N(R12e)SO2R12c, —N(R12e)C(O)OR12b, —N(R12e)C(O)N(R12b)2, or —N(R12e)SO2N(R12b)2, or two occurrences of R12b, taken together with a nitrogen atom to which they are bound, form an optionally substituted 4-7-membered heterocyclyl ring having 0-1 additional heteroatoms selected from nitrogen, oxygen, or sulfur;            each occurrence of R12b is independently hydrogen or an optionally substituted group selected from C1-C6 aliphatic, 3-10-membered cycloaliphatic, 4-10-membered heterocyclyl having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur, 6-10-membered aryl, or 5-10-membered heteroaryl having 0.1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur;            each occurrence of R12c is independently an optionally substituted group selected from C1-C6 aliphatic, 3-10-membered cycloaliphatic, 4-10-membered heterocyclyl having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur, 6-10-membered aryl, or 5-10-membered heteroaryl having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur;            each occurrence of R12d is independently hydrogen or an optionally substituted from 3-10-membered cycloaliphatic, 4-10-membered heterocyclyl having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur, 6-10-membered aryl, or 5-10-membered heteroaryl having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur;            each occurrence of R12e is independently hydrogen or an optionally substituted C1-6 aliphatic group;            each occurrence of V2 is independently —N(R12e)—, —O—, —S—, —S(O)—, —S(O)2—, —C(O)—, —C(O)O—, —C(O)N(R12e)—, S(O)2N(R12e)—, —OC(O)N(R12e)—, —N(R12e)C(O)—, —N(R12e)SO2—, —N(R12e)C(O)O—, —NR12eC(O)N(R12e)—, —N(R12e)SO2N(R12e)—, —OC(O)—, or —C(O)N(R12e)—O—; and            T2 is an optionally substituted C1-C6 alkylene chain wherein the alkylene chain optionally is interrupted by —N(R13)—, —O—, —S—, —S(O)—, —S(O)2—, —C(O)—, —C(O)O—, —C(O)N(R13)—, —S(O)2N(R13)—, —OC(O)N(R13)—, —N(R13)C(O)—, —N(R13)SO2—, —N(R13)C(O)O—, —NR13C(O)N(R13)—, —N(R13)S(O)2N(R13)—, —OC(O)—, or —C(O)N(R13)—O— or wherein T3 or a portion thereof optionally forms part of an optionally substituted 3-7 membered cycloaliphatic or heterocyclyl ring, wherein R13 is hydrogen or an optionally substituted C1-4aliphatic group; and                        c. HY is selected from:        
                wherein R10 is —R10b, —V1—R10c, -T1-R10b or —V1-T1-R10b wherein:                    V1 is —NR10a, —NR10a—C(O)—, —NR10a—C(S)—, —NR10a—C(NR10a)—, NR10aC(O)OR10a—, NR10aC(O)NR10a—, NR1aC(O)SR10a—, NR1aC(S)OR10a—, NR10aC(S)NR10a—, NR10aC(S)SR10a—, —NR10aC(NR10a)OR10a—, —NR10aC(NR10a)NR10a—, —NR10aS(O)2—, —NR10aS(O)2NR10a—, —C(O)—, —CO2—, —C(O)NR10a—, C(O)NR10a—, —SO2—, or —SO2NR10a—;            each occurrence of R10a is independently hydrogen or an optionally substituted group selected from C1-6aliphatic, 3-10-membered cycloaliphatic, 4-10-membered heterocyclyl having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur, 6-10-membered aryl, or 5-10-membered heteroaryl having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur;            T1 is an optionally substituted C1-C6 alkylene chain wherein the alkylene chain optionally is interrupted by —N(R10a)—, —O—, —S—, —S(O)—, —S(O)2—, —C(O)—, —C(O)O—, —C(O)N(R10a)—, —S(O)2N(R10a)—, —OC(O)N(R10a)—, —N(R10a)C(O)—, —N(R10a)SO2—, —N(R10a)C(O)O—, —NR10aC(O)N(R10a)—, —N(R10a)S(O)2N(R10a)—, —OC(O)—, or —C(O)N(R10a)—O— or wherein T1 forms part of an optionally substituted 3-7 membered cycloaliphatic or heterocyclyl ring;            each occurrence of R10b is independently hydrogen, halogen, —CN, —NO2, —N(R10a)2, —OR10a, —SR10a, —S(O)2R10a, —C(O)R10a, —C(O)OR10a, —C(O)N(R10a)2, —S(O)2N(R10a)2, —OC(O)N(R10a)2, —N(R10a)C(O)R10a, —N(R10a)SO2R10a, —N(R10aC(O)OR10a, —N(R10a)C(O)N(R10a)2, or —N(R10a)SO2N(R10a)2, or an optionally substituted group selected from 3-10-membered cycloaliphatic, 4-10-membered heterocyclyl having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur, 6-10-membered aryl, or 5-10-membered heteroaryl having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur;            each occurrence of R10c is independently hydrogen or an optionally substituted group selected from C1-6 aliphatic, 3-10-membered cycloaliphatic, 4-10-membered heterocyclyl having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur, 6-10-membered aryl, or 5-10-membered heteroaryl having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or            R10a and R10c taken together with a nitrogen atom to which they are bound form an optionally substituted 4-7-membered heterocyclyl ring having 0-1 additional heteroatoms independently selected from nitrogen, oxygen, or sulfur,            wherein each occurrence of X4, X5, and X6 is independently N or CR10,            or two adjacent groups selected from Y, R11, R10, X4, X5, and X6, taken together, form an optionally substituted group selected from 3-10-membered cycloaliphatic, 4-10-membered heterocyclyl having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur, 6-10-membered aryl, or 5-10-membered heteroaryl having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur, and            each occurrence of R11 is independently hydrogen, —C(O)R11a—, —CO2R11a—, —C(O)NR11a—, C(O)NR11aO—, —SO2R11a—, —SO2NR11a—, or an optionally substituted group selected from C1-6aliphatic, 3-10-membered cycloaliphatic, 4-10-membered heterocyclyl having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur, 6-10-membered aryl, or 5-10-membered heteroaryl having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur;            wherein each occurrence of R11a is independently hydrogen or an optionally substituted group selected from C1-6aliphatic, 3-10-membered cycloaliphatic, 4-10-membered heterocyclyl having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur, 6-10-membered aryl, or 5-10-membered heteroaryl having 1-5 heteroatoms independently selected from nitrogen; oxygen, or sulfur; and                        Y is N or CR10.        
The invention also provides [23], compounds of [22], wherein HY is selected from:
                wherein each HY group is optionally additionally substituted with one or more occurrences of R10.        
The invention also provides [24], compounds of [23], wherein HY is selected from:
                wherein each HY group is optionally additionally substituted with one or more occurrences of R10         
The invention also provides [25], compounds of [24], wherein HY is selected from:
                wherein each HY group is optionally additionally substituted with one or more occurrences of R10.        
The invention also provides [26], compounds of [25], wherein HY is selected from:
                wherein each HY group is optionally additionally substituted with one or more occurrences of R10.        
The invention also provides [27], compounds of [22], [23], [24], [25], or [26], wherein R2 is an optionally substituted 6-10-membered aryl or 5-10-membered heteroaryl having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur.
The invention also provides [28], compounds of [22], [23], [24], [25], or [26], wherein R2 is a phenyl group substituted with 1-3 independent occurrences of halo, C1-3 alkyl, CN, —OC1-3 alkyl, —OC1-3haloalkyl, —NHC(O)C1-3 alkyl, —NHC(O)NHC1-3 alkyl, NHS(O)2C1-3 alkyl, or —C(O)H.
The invention also provides [29], compounds of [1], for compounds of I-A, wherein G1 is CR3, HY is an optionally substituted 6-membered nitrogen-containing heteroaryl group, and R1 is —NHCOR4, —NHSO2R4, —NHCON(R4)2, —NHCOOR4, —NHSO2N(R4)2, or —NHSO2OR4.
The invention also provides [30], compounds of [29], wherein:                G1 is CH:        HY is        
                R1 is —NHCOR4, —NHSO2R4, —NHCON(R4)2, —NHCOOR4, —NHSO2N(R4)2, or —NHSO2OR4,        R4 is C1-6 alkyl, and        R2 is a C6-18 aryl group which is optionally substituted by halogen.        
The invention also provides [31], compounds of [30], wherein:                G1 is CH;        HY is        
                                    R11 is C1-6arkylcarbonyl,            R1 is —NHCOR4, R4 is C1-6 alkyl and            R2 is a C6-18 aryl group which is optionally substituted by halogen.                        
The invention also provides [32], compounds of [1], for compounds of formula I-A, wherein G1 is CR3, HY is an optionally substituted bicyclic or polycyclic nitrogen-containing heteroaryl group, and R1 is CY, —CON(R4)2, —NHCOR4, —NHSO2R4, —NHCON(R4)2, —NHCOOR4, —NHSO2N(R4)2, or —NHSO2OR4.
The invention also provides [33], compounds of [32], wherein HY is selected from:
                wherein each HY group is optionally additionally substituted with one or more occurrences of R10.        
The invention also provides [34], compounds of [33], wherein HY is selected from:
                wherein each HY group is optionally additionally substituted with one or more occurrences of R10.        
The invention also provides [35], compounds of [34], wherein R1 is CY, and CY is
R2 is an optionally substituted 6-10-membered aryl or 5-10-membered heteroaryl having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur.
The invention also provides [36], compounds of [35], wherein R2 is a phenyl group substituted with 1-3 independent occurrences of halo, C1-3 alkyl, CN, C1-3haloalkyl, —OC1-3 alkyl, —OC1-3 haloalkyl, —NHC(O)C1-3 alkyl, —NHC(O)NHC1-3 alkyl, NHS(O)2C1-3alkyl, or —C(O)H.
The invention also provides [37], compounds of [35], wherein X1 is N and X2 and X3 are CH.
The invention also provides [38], compounds of [35], wherein X1 and X2 are N, and X3 is CH.
The invention also provides [39], compounds of [1], for compounds of formula I-A, wherein G1 is N, HY is an optionally substituted nitrogen-containing heteroaryl group, and R1 is —CON(R4)2, —NHCOR4, —NHSO2R4, —NHCON(R4)2, —NHCOOR4, —NHSO2N(R4)2, or —NHSO2OR4.
The invention also provides [40], compounds of [39], wherein R1 is —NHSO2R4, and R4 is C1-6alkyl.
The invention also provides [41], compounds of [40], wherein R1 is CY, and CY is
R2 is an optionally substituted 6-10-membered aryl or 5-10-membered heteroaryl having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur.
The invention also provides [42], compounds of [40], wherein R2 is a phenyl group substituted with 1-3 independent occurrences of halo, C1-3 alkyl, CN, C1-3haloalkyl, —OC1-3 alkyl, —OC1-3 haloalkyl, —NHC(O)C1-3 alkyl, —NHC(O)NHC1-3 alkyl, NHS(O)2C1-3alkyl, or —C(O)H.
The invention also provides [43], compounds of [42], wherein X1 is N and X2 and X3 are CH.
The invention also provides [44], compounds of [42], wherein X1 and X2 are N, and X3 is CH.
The invention also provides [45], compounds of [1], wherein compounds are represented by formula I-B.
The invention also provides [46], compounds of [45] wherein G1 is CH.
The invention also provides [47], compounds of [1] having formula III:
                wherein R10d is hydrogen or optionally substituted C1-4alkyl, and R10e is R10.        
The invention also provides [48], compounds of [47]: wherein R10e is —V1—R10c, or halogen.
The invention also provides [49], compounds of [47], wherein R10d is hydrogen or C1-6 alkyl such as methyl, R10e is H, hydroxy, C1-6alkyl, C1-6 alkoxy optionally substituted by a group selected from hydroxy, C1-6 alkyl-carbonylamino and amino-C1-6 alkyl-carbonylamino, C6-18 aryl-C1-4alkyl-oxy, 4- to 7-membered monocyclic aromatic heterocyclyl-C1-4 alkyl-oxy containing, as a ring constituting atom besides carbon atom, 1 to 4 heteroatoms selected from an oxygen atom, a sulfur atom and a nitrogen atom optionally substituted by C1-6 alkyl optionally substituted by halogen and 4- to 7-membered monocyclic non-aromatic heterocyclyl-C1-4 alkyl-oxy containing, as a ring constituting atom besides carbon atom, 1 to 4 heteroatoms selected from an oxygen atom, a sulfur atom and a nitrogen atom optionally substituted by a group selected from halogen, C1-6 alkyl, C1-6 alkylsulfonyloxy and C1-6 alkyl-carbonyl optionally substituted by hydroxyl, R3 is H, and R4′ is H.
The invention also provides [50], compounds of [47], [48], or [49], wherein X1 is N and X2 and X3 are H.
The invention also provides [51], compounds of [47], [48], or [49], wherein X1 and X2 are N, and X3 is H.
The invention also provides [52], compounds of [47], [48], or [49], wherein R2 is an optionally substituted 6-10-membered aryl or 5-10-membered heteroaryl having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur.
The invention also provides [53], compounds of [47], [48], or [49], wherein: R2 is a phenyl group substituted with 1-3 independent occurrences of halo, C1-3 alkyl, CN, C1-3haloalkyl, —OC1-3 alkyl, —OC1-3haloalkyl, —NHC(O)C1-3 alkyl, —NHC(O)NHC1-3alkyl, NHS(O)2C1-3alkyl, or —C(O)H.
The invention also provides [54], compounds of [1],
or a pharmaceutically acceptable salt thereof, wherein:                G1 is N or CR3, wherein R3 is H, —CN, halogen, —Z—R5, C1-6 aliphatic, or 3-10-membered cycloaliphatic, wherein:                    Z is selected from an optionally substituted C1-3 alkylene chain, —O—, —N(R3a)—, —S—, —S(O)—, —S(O)2—, —C(O)—, —CO2—, —C(O)NR3a—, —N(R3a)C(O)—, —N(R3a)CO2—, —S(O)2NR3a—, —N(R3a)S(O)2—, —OC(O)N(R3a)—, —N(R3a)C(O)NR3a—, —N(R3a)S(O)2N(R3a)—, or —OC(O)—;            R3a is hydrogen or an optionally substituted C1-4 aliphatic, and            R5 is an optionally substituted group selected from C1-6 aliphatic, 3-10-membered cycloaliphatic, 4-10-membered heterocyclyl having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur, 6-10-membered aryl, or 5-10-membered heteroaryl having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur;                        R1 is CY, —CON(R4)2, —NHCOR4, —NHSO2R4, —NHCON(R4)2, —NHCOOR4, —NHSO2N(R4)2, or —NHSO2OR4, wherein:                    CY is                        
                                     wherein:            X1, X2, and X3, are each independently N, O, S, or CR7, provided that only one of X1, X2, or X3 may be O or S,            G2 is —N═ or —NR4′—, wherein:            each occurrence of R4 and R4′ is independently H, —Z2—R6, optionally substituted C1-6 aliphatic, or optionally substituted 3-10-membered cycloaliphatic, wherein:                            Z2 is selected from an optionally substituted C1-3 alkylene chain, —S(O)—, —S(O)2—, —C(O)—, —C(O)NR4a—, or —S(O)2NR4a—.                R4a is hydrogen or an optionally substituted C1-4 aliphatic, and                R6 is an optionally substituted group selected from C1-6 aliphatic, 3-10-membered cycloaliphatic, 4-10-membered heterocyclyl having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur, 6-10-membered aryl, or 5-10-membered heteroaryl having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur;                                    each occurrence of R7 is independently hydrogen, —CN, halogen, —Z3—R8, C1-6 aliphatic, or 3-10-membered cycloaliphatic, wherein:                            Z3 is selected from an optionally substituted C1-3 alkylene chain, —O—, —N(R7a)—, —S—, —S(O)—, —S(O)2—, —C(O)—, —C(O)NR7a—, —N(R7a)C(O)—, —N(R7a)CO2—, —S(O)2NR7a—, —N(R7a)S(O)2—, —OC(O)N(R7a)—, —N(R7a)C(O)NR7a—, —N(R7a)S(O)2N(R7a)—, or —OC(O)—.                R7a is hydrogen or an optionally substituted C1-4 aliphatic, and                R8 is an optionally substituted group selected from C1-6 aliphatic, 3-10-membered cycloaliphatic, 4-10-membered heterocyclyl having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur, 6-10-membered aryl, or 5-10-membered heteroaryl having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur,                                                R2 is halogen, —W—R9, or —R9, wherein:                    W is selected from an optionally substituted C1-3 alkylene chain, —O—, —N(R2a)—, —S—, —S(O)—, —S(O)2—, —C(O)—, —N(R2a)C(O)—, —C(O)NR2a—, —N(R2a)CO2—, —S(O)2NR2a—, —N(R2a)S(O)2—, —OC(O)N(R2a)—, —N(R2a)C(O)NR2a—, —N(R2a)S(O)2N(R2a)—, or —OC(O)—.            R2a is hydrogen or an optionally substituted C1-4 aliphatic, and                        R9 is an optionally substituted group selected from C1-6 aliphatic, 3-10-membered cycloaliphatic, 4-10-membered heterocyclyl having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur, 6-10-membered aryl, or 5-10-membered heteroaryl having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur; and        HY is selected from:        
                wherein each HY group is optionally additionally substituted with one or more occurrences of R10.        
The invention also provides [55], compounds of [54], wherein HY is selected from:
                wherein each HY group is optionally additionally substituted with one or more occurrences of R10.        
The invention also provides [56], compounds of [54], wherein R1 is CY, and CY is

The invention also provides [57], compounds of [54], wherein R1 is —CON(R4)2, —NHCOR4, —NHSO2R4, —NHCON(R4)2, —NHCOOR4, —NHSO2N(R4)2, or —NHSO2OR4.
The invention also provides [58], compounds of [54], [55], [56], or [57], wherein G1 is CR3.
The invention also provides [59], compounds of [54], [55], [56], or [57], wherein G1 is N.
The invention also provides [60], compounds of [54], [55], [56], or [57], wherein R2 is a 3-10-membered cycloaliphatic, 4-10-membered heterocyclyl having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur 6-10-membered aryl, or 5-10-membered heteroaryl having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur, optionally substituted with 1-4 independent occurrences of R12, wherein R12 is —R12a, -T2-R12d, or —V2-T2-R12d, and:                each occurrence of R9a is independently halogen, —CN, —NO2, —R12c, —N(R12b)2, —OR12b, —SR12c, —S(O)2R12c, —C(O)R12b, —C(O)OR12b, —C(O)N(R12b)2, —S(O)2N(R12)2, —OC(O)N(R12b)2, —N(R12e)C(O)R12b, —N(R12e)SO2R12c, —N(R12e)C(O)OR12b, —N(R12e)C(O)N(R12b)2, or —N(R12e)SO2N(R12b)2, or two occurrences of R12b, taken together with a nitrogen atom to which they are bound, form an optionally substituted 4-7-membered heterocyclyl ring having 0-1 additional heteroatoms selected from nitrogen, oxygen, or sulfur;                    each occurrence of R12b is independently hydrogen or an optionally substituted group selected from C1-C6 aliphatic, 3-10-membered cycloaliphatic, 4-10-membered heterocyclyl having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur, 6-10-membered aryl, or 5-10-membered heteroaryl having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur;            each occurrence of R12c is independently an optionally substituted group selected from C1-C6 aliphatic, 3-10-membered cycloaliphatic, 4-10-membered heterocyclyl having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur, 6-10-membered aryl, or 5-10-membered heteroaryl having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur;            each occurrence of R12d is independently hydrogen or an optionally substituted from 3-10-membered cycloaliphatic, 4-10-membered heterocyclyl having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur, 6-10-membered aryl, or 5-10-membered heteroaryl having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur;            each occurrence of R12e is independently hydrogen or an optionally substituted C1-6 aliphatic group;            each occurrence of V2 is independently —N(R12e)—, —O—, —S—, —S(O)—, —S(O)2—, —C(O)—, —C(O)O—, —C(O)N(R12e)—, —S(O)2N(R12e)—, —OC(O)N(R12e)—, —N(R12e)C(O)—, —N(R12e)SO2—, —N(R12e)C(O)O—, —NR12eC(O)N(R12e)—, —N(R12e)SO2N(R12e)—, —OC(O)—, or —C(O)N(R12e)—O—; and            T2 is an optionally substituted C1-C6 alkylene chain wherein the alkylene chain optionally is interrupted by —N(R13)—, —O—, —S—, —S(O)—, —S(O)2—, —C(O)—, —C(O)O—, —C(O)N(R13)—, —S(O)2N(R13)—, —OC(O)N(R13)—, —N(R13)C(O)—, —N(R13)SO2—, —N(R13)C(O)O—, —NR13C(O)N(R13)—, —N(R13)S(O)2N(R13)—, —OC(O)—, or —C(O)N(R13)—O— or wherein T3 or a portion thereof optionally forms part of an optionally substituted 3-7 membered cycloaliphatic or heterocyclyl ring, wherein R13 is hydrogen or an optionally substituted C1-4aliphatic group.                        
The invention also provides [61], compounds of [54], [55], [56], or [57], wherein R2 is an optionally substituted 6-10-membered aryl or 5-10-membered heteroaryl having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur.
The invention also provides [62], compounds of [54] wherein: R2 is a phenyl group substituted with 1-3 independent occurrences of halogen, C1-3 alkyl, CN, C1-3haloalkyl, —OC1-3 alkyl, —OC1-3haloalkyl, —NHC(O)C1-3 alkyl, —NHC(O)NHC1-3 alkyl, NHS(O)2C1-3 alkyl, or —C(O)H.
The invention also provides [63], compounds of [62], wherein R2 is halogen.
The invention also provides [64], compounds of [54] wherein when R1 is CY, X1 is N, G2 is NR4′, and X2 and X3 are CR7.
The invention also provides [65], compounds of [54], wherein when R1 is CY, X1 and X2 are N, G2 is NR4 and X3 is CR7.
The invention also provides [66], compounds of [65], wherein R7 is H or NH2.
The invention also provides [67] a composition comprising compounds [1], [2], [29], [31], [37], [41], [43], or [52], and a pharmaceutically acceptable carrier.
The invention also provides [68] a method of treating a proliferative disorder in a patient comprising administering to said patient a therapeutically effective amount of compounds [1], [2], [29], [31], [37], [41], [43], or [52].
The invention also provides [69] the method of claim [68], wherein the proliferative disorder is breast cancer, bladder cancer, colon cancer, glioma, glioblastoma, lung cancer, hepatocellular cancer, gastric cancer, melanoma, thyroid cancer, endometrial cancer, renal cancer, cervical cancer, pancreatic cancer, esophageal cancer, prostate cancer, brain cancer, or ovarian cancer.
The invention also provides [70] a method of treating an inflammatory or cardiovascular disorder in a patient comprising administering to said patient a therapeutically effective amount of compounds [1], [2], [29], [31], [37], [41], [43], or [52].
The invention also provides [71], wherein the inflammatory or cardiovascular disorder is selected from allergies/anaphylaxis, acute and chronic inflammation, rheumatoid arthritis; autoimmunity disorders, thrombosis, hypertension, cardiac hypertrophy, and heart failure.
The invention also provides [72], a method for inhibiting PI3K or mTor activity in a patient comprising administering a composition comprising an amount of compounds [1], [2], [29], [31], [37], [41], [43], or [52], effective to inhibit PI3K or mTor activity in the patient.
2. Detailed Description of Compounds of the Invention:
Compounds of this invention include those described generally for formula I-A and I-B above, and are further illustrated by the classes, subclasses, and species disclosed herein. As used herein, the following definitions shall apply unless otherwise indicated.
As described herein, compounds of the invention may be optionally substituted with one or more substituents, such as are illustrated generally above, or as exemplified by particular classes, subclasses, and species of the invention. It will be appreciated that the phrase “optionally substituted” is used interchangeably with the phrase “substituted or unsubstituted.” In general, the term “substituted”, whether preceded by the term “optionally” or not, means that a hydrogen radical of the designated moiety is replaced with the radical of a specified substituent, provided that the substitution results in a stable or chemically feasible compound. The term “substitutable”, when used in reference to a designated atom, means that attached to the atom is a hydrogen radical, which hydrogen atom can be replaced with the radical of a suitable substituent. Unless otherwise indicated, an “optionally substituted” group may have a substituent at each substitutable position of the group, and when more than one position in any given structure may be substituted with more than one substituent selected from a specified group, the substituent may be either the same or different at every position. Combinations of substituents envisioned by this invention are preferably those that result in the formation of stable or chemically feasible compounds.
A stable compound or chemically feasible compound is one in which the chemical structure is not substantially altered when kept at a temperature from about −80° C. to about +40°, in the absence of moisture or other chemically reactive conditions, for at least a week, or a compound which maintains its integrity long enough to be useful for therapeutic or prophylactic administration to a patient.
The phrase “one or more substituents”, as used herein, refers to a number of substituents that equals from one to the maximum number of substituents possible based on the number of available bonding sites, provided that the above conditions of stability and chemical feasibility are met.
As used herein, the term “independently selected” means that the same or different values may be selected for multiple instances of a given variable in a single compound. As used herein, “a 3-7-membered saturated, partially unsaturated, or aromatic monocyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or an 8-10-membered partially unsaturated, or aromatic bicyclic ring system having 0-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur” includes cycloaliphatic, heterocyclic, aryl and heteroaryl rings.
As used herein, the term “aromatic” includes aryl and heteroaryl groups as described generally below and herein.
The term “aliphatic” or “aliphatic group”, as used herein, means an optionally substituted straight-chain or branched C1-12 hydrocarbon, or a cyclic C1-12 hydrocarbon which is completely saturated or which contains one or more units of unsaturation, but which is not aromatic (also referred to herein as “carbocycle”, “cycloaliphatic”, “cycloalkyl”, or “cycloalkenyl”). For example, suitable aliphatic groups include optionally substituted linear, branched or cyclic alkyl, alkenyl, alkynyl groups and hybrids thereof, such as (cycloalkyl)alkyl, (cycloalkenyl)alkyl, or (cycloalkyl)alkenyl. Unless otherwise specified, in various embodiments, aliphatic groups have 1-12, 1-10, 1-8, 1-6, 1-4, 1-3, or 1-2 carbon atoms.
The term “alkyl”, used alone or as part of a larger moiety, refers to an optionally substituted straight or branched chain hydrocarbon group having 1-12, 1-10, 1-8, 1-6, 1-4, 1-3, or 1-2 carbon atoms.
The term “alkenyl”, used alone or as part of a larger moiety, refers to an optionally substituted straight or branched chain hydrocarbon group having at least one double bond and having 2-12, 2-10, 2-8, 2-6, 2-4, or 2-3 carbon atoms.
The term “alkynyl”, used alone or as part of a larger moiety, refers to an optionally substituted straight or branched chain hydrocarbon group having at least one triple bond and having 2-12, 2-10, 2-8, 2-6, 2-4, or 2-3 carbon atoms.
The terms “cycloaliphatic”, “carbocycle”, “carbocyclyl”, “carbocyclo”, or “carbocyclic”, used alone or as part of a larger moiety, refer to an optionally substituted saturated or partially unsaturated cyclic aliphatic ring system having from 3 to about 14 ring carbon atoms. In some embodiments, the cycloaliphatic group is an optionally substituted monocyclic hydrocarbon having 3-10, 3-8, 3-7, or 3-6 ring carbon atoms. Cycloaliphatic groups include, without limitation, optionally substituted cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl, cycloheptenyl, cyclooctyl, cyclooctenyl, or cyclooctadienyl. The terms “cycloaliphatic”, “carbocycle”, “carbocyclyl”, “carbocyclo”, or “carbocyclic” also include optionally substituted bridged or fused bicyclic rings having 6-12, 6-10, or 6-8 ring carbon atoms, wherein any individual ring in the bicyclic system has 3-8 ring carbon atoms.
The term “cycloalkyl” refers to an optionally substituted saturated ring system of about 3 to about 10 ring carbon atoms. Exemplary monocyclic cycloalkyl rings include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl.
The term “cycloalkenyl” refers to an optionally substituted non-aromatic monocyclic or multicyclic ring system containing at least one carbon-carbon double bond and having about 3 to about 10 carbon atoms. Exemplary monocyclic cycloalkenyl rings include cyclopentyl, cyclohexenyl, and cycloheptenyl.
The terms “haloaliphatic”, “haloalkyl”, “haloalkenyl” and “haloalkoxy” refer to an aliphatic, alkyl, alkenyl or alkoxy group, as the case may be, which is substituted with one or more halogen atoms. As used herein, the term “halogen” or “halo” means F, Cl, Br, or I. The term “fluoroaliphatic” refers to a haloaliphatic wherein the halogen is fluoro, including perfluorinated aliphatic groups. Examples of fluoroaliphatic groups include, without limitation, fluoromethyl, difluoromethyl, trifluoromethyl, 2-fluoroethyl, 2,2,2-trifluoroethyl, 1,1,2-trifluoroethyl, 1,2,2-trifluoroethyl, and pentafluoroethyl.
The term “heteroatom” refers to one or more of oxygen, sulfur, nitrogen, phosphorus, or silicon (including, any oxidized form of nitrogen, sulfur, phosphorus, or silicon; the quaternized form of any basic nitrogen or; a substitutable nitrogen of a heterocyclic ring, for example N (as in 3,4-dihydro-2H-pyrrolyl), NH (as in pyrrolidinyl) or NR+ (as in N-substituted pyrrolidinyl)).
The terms “aryl” and “ar-”, used alone or as part of a larger moiety, e.g., “aralkyl”, “aralkoxy”, or “aryloxyalkyl”, refer to an optionally substituted C6-14aromatic hydrocarbon moiety comprising one to three aromatic rings. Preferably, the aryl group is a C6-10aryl group. Aryl groups include, without limitation, optionally substituted phenyl, naphthyl, or anthracenyl. The terms “aryl” and “ar-”, as used herein, also include groups in which an aryl ring is fused to one or more cycloaliphatic rings to form an optionally substituted cyclic structure such as a tetrahydronaphthyl, indenyl, or indanyl ring. The term “aryl” may be used interchangeably with the terms “aryl group”, “aryl ring”, and “aromatic ring”.
An “aralkyl” or “arylalkyl” group comprises an aryl group covalently attached to an alkyl group, either of which independently is optionally substituted. Preferably, the aralkyl group is C6-10 arylC1-4alkyl, including, without limitation, benzyl, phenethyl, and naphthylmethyl.
The terms “heteroaryl” and “heteroar-”, used alone or as part of a larger moiety, e.g., “heteroaralkyl”, or “heteroaralkoxy”, refer to groups having 5 to 14 ring atoms, preferably 5-10, more preferably 5, 6, 9, or 10 ring atoms; having 6, 10, or 14 π electrons shared in a cyclic array; and having, in addition to carbon atoms, from one to five heteroatoms. A heteroaryl group may be mono-, bi-, tri-, or polycyclic, preferably mono-, bi-, or tricyclic, more preferably mono- or bicyclic. The term “heteroatom” refers to nitrogen, oxygen, or sulfur, and includes any oxidized form of nitrogen or sulfur, and any quaternized form of a basic nitrogen. For example, a nitrogen atom of a heteroaryl may be a basic nitrogen atom and may also be optionally oxidized to the corresponding N-oxide. When a heteroaryl is substituted by a hydroxy group, it also includes its corresponding tautomer. The terms “heteroaryl” and “heteroar-”, as used herein, also include groups in which a heteroaromatic ring is fused to one or more aryl, cycloaliphatic, or heterocycloaliphatic rings. Nonlimiting examples of heteroaryl groups include thienyl, furanyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, thiadiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolizinyl, purinyl, naphthyridinyl, pteridinyl, indolyl, isoindolyl, benzothienyl, benzofuranyl, dibenzofuranyl, indazolyl, benzimidazolyl, benzthiazolyl, quinolyl, isoquinolyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, 4H-quinolizinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl, phenoxazinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, and pyrido[2,3-b]-1,4-oxazin-3(4H)-one. The term “heteroaryl” may be used interchangeably with the terms “heteroaryl ring”, “heteroaryl group”, or “heteroaromatic”, any of which terms include rings that are optionally substituted. The term “heteroaralkyl” refers to an alkyl group substituted by a heteroaryl, wherein the alkyl and heteroaryl portions independently are optionally substituted.
As used herein, the terms “heterocycle”, “heterocyclyl”, “heterocyclic radical”, and “heterocyclic ring” are used interchangeably and refer to a 3- to 10-, preferably 3- to 7-, 4- to 7-, or 4- to 10-membered heterocycle such as a stable 3- to 8-membered monocyclic or 7-10-membered bicyclic heterocyclic moiety that is either saturated or partially unsaturated, and having, in addition to carbon atoms, one or more, preferably one to four, heteroatoms, as defined above. When used in reference to a ring atom of a heterocycle, the term “nitrogen” includes a substituted nitrogen. As an example, in a saturated or partially unsaturated ring having 0-3 heteroatoms selected from oxygen, sulfur or nitrogen, the nitrogen may be N (as in 3,4-dihydro-2H-pyrrolyl), NH (as in pyrrolidinyl), or NR+ (as in N-substituted pyrrolidinyl).
A heterocyclic ring can be attached to its pendant group at any heteroatom or carbon atom that results in a stable structure and any of the ring atoms can be optionally substituted. Examples of such saturated or partially unsaturated heterocyclic radicals include, without limitation, tetrahydrofuranyl, tetrahydrothienyl, piperidinyl, decahydroquinolinyl, oxazolidinyl, piperazinyl, dioxanyl, dioxolanyl, diazepinyl, oxazepinyl, thiazepinyl, morpholinyl, and thiamorpholinyl. A heterocyclyl group may be mono-, bi-, tri-, or polycyclic, preferably mono-, bi-, or tricyclic, more preferably mono- or bicyclic. The term “heterocyclylalkyl” refers to an alkyl group substituted by a heterocyclyl, wherein the alkyl and heterocyclyl portions independently are optionally substituted. Additionally, a heterocyclic ring also includes groups in which the heterocyclic ring is fused to one or more aryl rings.
As used herein, the term “partially unsaturated” refers to a ring, moiety that includes at least one double or triple bond between ring atoms. The term “partially unsaturated” is intended to encompass rings having multiple sites of unsaturation, but is not intended to include aromatic (e.g., aryl or heteroaryl) moieties, as herein defined.
The term “alkylene” refers to a bivalent alkyl group. An “alkylene chain” is a polymethylene group, i.e., —(CH2)n—, wherein n is a positive integer, preferably from 1 to 6, from 1 to 4, from 1 to 3, from 1 to 2, or from 2 to 3. An optionally substituted alkylene chain is a polymethylene group in which one or more methylene hydrogen atoms is optionally replaced with a substituent. Suitable substituents include those described below for a substituted aliphatic group and also include those described in the specification herein. It will be appreciated that two substituents of the alkylene group may be taken together to form a ring system. In certain embodiments, two substituents can be taken together to form a 3-7-membered ring. The substituents can be on the same or different atoms.
An alkylene chain also can be optionally interrupted by a functional group. An alkylene chain is “interrupted” by a functional group when an internal methylene unit is interrupted by the functional group. Examples of suitable “interrupting functional groups” are described in the specification and claims herein.
For purposes of clarity, all bivalent groups described herein, including, e.g., the alkylene chain linkers described above, are intended to be read from left to right, with a corresponding left-to-right reading of the formula or structure in which the variable appears.
An aryl (including aralkyl, aralkoxy, aryloxyalkyl and the like) or heteroaryl (including heteroaralkyl and heteroarylalkoxy and the like) group may contain one or more substituents and thus may be “optionally substituted”. In addition to the substituents defined above and herein, suitable substituents on the unsaturated carbon atom of an aryl or heteroaryl group also include and are generally selected from -halo, —NO2, —CN, —R+, —C(R+)═C(R+)2, —C≡C—R+, —OR+, —SRo, —S(O)Ro, —SO2Ro, —SO3R+, —SO2N(R+)2, —N(R+)2, —NR+C(O)R+, —NR+C(S)R+, —NR+C(O)N(R+)2, —NR+C(S)N(R+)2, —N(R+)C(═NR+)—N(R+)2, —N(R+)C(═NR+)—Ro, —NR+CO2R+, —NR+SO2Ro, —NR+SO2N(R+)2, —O—C(O)R+, —O—CO2R+, —OC(O)N(R+)2, —C(O)R+, —C(S)Ro, —CO2R+, —C(O)—C(O)R+, —C(O)N(R+)2, —C(S)N(R+)2, —C(O)N(R+)—OR+, —C(O)N(R+)C(═NR+)—N(R+)2, —N(R+)C(═NR+)—N(R+)—C(O)R+, —C(═NR)—N(R+)2, —C(═NR+)—OR+, —N(R+)—N(R+)2, —C(═NR+)—N(R+)—OR+, —C(Ro)═N—OR+, —P(O)(R+)2, —P(O)(OR+)2, —O—P(O)—OR+, and —P(O)(NR+)—N(R+)2, wherein R+, independently, is hydrogen or an optionally substituted aliphatic, aryl, heteroaryl, cycloaliphatic, or heterocyclyl group, or two independent occurrences of R+ are taken together with their intervening atom(s) to form an optionally substituted 5-7-membered aryl, heteroaryl, cycloaliphatic, or heterocyclyl ring. Each Ro is an optionally substituted aliphatic, aryl, heteroaryl, cycloaliphatic, or heterocyclyl group.
An aliphatic or heteroaliphatic group, or a non-aromatic carbycyclic or heterocyclic ring may contain one or more substituents and thus may be “optionally substituted”. Unless otherwise defined above and herein, suitable substituents on the saturated carbon of an aliphatic or heteroaliphatic group, or of a non-aromatic carbocyclic or heterocyclic ring are selected from those listed above for the unsaturated carbon of an aryl or heteroaryl group and additionally include the following: ═O, ═S, ═C(R*)2, ═N—N(R*)2, ═N—OR*, ═N—NHC(O)R*, ═N—NHCO2Ro═N—NHSO2Ro or ═N—R* where Ro is defined above, and each R* is independently selected from hydrogen or an optionally substituted C1-6 aliphatic group.
In addition to the substituents defined above and herein, optional substituents on the nitrogen of a non-aromatic heterocyclic ring also include and are generally selected from —R+, —N(R+)2, —C(O)R+, —C(O)OR+, —C(O)C(O)R+, —C(O)CH2C(O)R+, —S(O)2R+, —S(O)2N(R+)2, —C(S)N(R+)2, —C(═NH)—N(R+)2, or —N(R+)S(O)2R+; wherein each R+ is defined above. A ring nitrogen atom of a heteroaryl or non-aromatic heterocyclic ring also may be oxidized to form the corresponding N-hydroxy or N-oxide compound. A nonlimiting example of such a heteroaryl having an oxidized ring nitrogen atom is N-oxidopyridyl.
As detailed above, in some embodiments, two independent occurrences of R+ (or any other variable similarly defined in the specification and claims herein), are taken together with their intervening atom(s) to form a monocyclic or bicyclic ring selected from 3-13-membered cycloaliphatic, 3-12-membered heterocyclyl having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur, 6-10-membered aryl, or 5-10-membered heteroaryl having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur.
Exemplary rings that are formed when two independent occurrences of R+ (or any other variable similarly defined in the specification and claims herein), are taken together with their intervening atom(s) include, but are not limited to the following: a) two independent occurrences of R+ (or any other variable similarly defined in the specification or claims herein) that are bound to the same atom and are taken together with that atom to form a ring, for example, N(R+)2, where both occurrences of R+ are taken together with the nitrogen atom to form a piperidin-1-yl, piperazin-1-yl, or morpholin-4-yl group; and b) two independent occurrences of R+ (or any other variable similarly defined in the specification or claims herein) that are bound to different atoms and are taken together with both of those atoms to form a ring, for example where a phenyl group is substituted with two occurrences of
these two occurrences of R+ are taken together with the oxygen atoms to which they are bound to form a fused 6-membered oxygen containing ring:
It will be appreciated that a variety of other rings (e.g., spiro and bridged rings) can be formed when two independent occurrences of R+ (or any other variable similarly defined in the specification and claims herein) are taken together with their intervening atom(s) and that the examples detailed above are not intended to be limiting.
Unless otherwise stated, structures depicted herein are also meant to include all isomeric (e.g., enantiomeric, diastereomeric, and geometric (or conformational)) forms of the structure; for example, the R and S configurations for each asymmetric center, (Z) and (E) double bond isomers, and (Z) and (E) conformational isomers. Therefore, single stereochemical isomers as well as enantiomeric, diastereomeric, and geometric (or conformational) mixtures of the present compounds are within the scope of the invention. Unless otherwise stated, all tautomeric forms of the compounds of the invention are within the scope of the invention. Additionally, unless otherwise stated, structures depicted herein are also meant to include compounds that differ only in the presence of one or more isotopically enriched atoms. For example, compounds having the present structures except for the replacement of hydrogen by deuterium or tritium, or the replacement of a carbon by a 13C- or 14C-enriched carbon are within the scope of this invention. Such compounds are useful, for example, as analytical tools or probes in biological assays.
It is to be understood that, when a disclosed compound has at least one chiral center, the present invention encompasses one enantiomer of inhibitor free from the corresponding optical isomer, racemic mixture of the inhibitor and mixtures enriched in one enantiomer relative to its corresponding optical isomer. When a mixture is enriched in one enantiomer relative to its optical isomers, the mixture contains, for example, an enantiomeric excess of at least 50%, 75%, 90%, 95% 99% or 99.5%.
The enantiomers of the present invention may be resolved by methods known to those skilled in the art, for example by formation of diastereoisomeric salts which may be separated, for example, by crystallization; formation of diastereoisomeric derivatives or complexes which may be separated, for example, by crystallization, gas-liquid or liquid chromatography; selective reaction of one enantiomer with an enantiomer-specific reagent, for example enzymatic esterification; or gas-liquid or liquid chromatography in a chiral environment, for example on a chiral support for example silica with a bound chiral ligand or in the presence of a chiral solvent. Where the desired enantiomer is converted into another chemical entity by one of the separation procedures described above, a further step is required to liberate the desired enantiomeric form. Alternatively, specific enantiomers may be synthesized by asymmetric synthesis using optically active reagents, substrates, catalysts or solvents, or by converting one enantiomer into the other by asymmetric transformation.
When a disclosed compound has at least two chiral centers, the present invention encompasses a diastereomer free of other diastereomers, a pair of diastereomers free from other diasteromeric pairs, mixtures of diasteromers, mixtures of diasteromeric pairs, mixtures of diasteromers in which one diastereomer is enriched relative to the other diastereomer(s) and mixtures of diasteromeric pairs in which one diastereomeric pair is enriched relative to the other diastereomeric pair(s). When a mixture is enriched in one diastereomer or diastereomeric pair(s) relative to the other diastereomers or diastereomeric pair(s), the mixture is enriched with the depicted or referenced diastereomer or diastereomeric pair(s) relative to other diastereomers or diastereomeric pair(s) for the compound, for example, by a molar excess of at least 50%, 75%, 90%, 95%, 99% or 99.5%.
The diastereoisomeric pairs may be separated by methods known to those skilled in the art, for example chromatography or crystallization and the individual enantiomers within each pair may be separated as described above. Specific procedures for chromatographically separating diastereomeric pairs of precursors used in the preparation of compounds disclosed herein are provided the examples herein.
In general, compounds of the invention are represented by formula (I-A) or (I-B):
or a pharmaceutically acceptable salt thereof, wherein:                G1 is N or CR3, wherein R3 is H, —CN, halogen, C1-6 aliphatic, or 3-10-membered cycloaliphatic, wherein:                    Z is selected from an optionally substituted C1-3 alkylene chain, —O—, —N(R3a)—, —S—, —S(O)—, —S(O)2—, —C(O)—, —CO2—, —C(O)NR3a—, —N(R3a)C(O)—, —N(R3a)CO2—, —S(O)2NR3a—, —N(R3a)S(O)2—, —OC(O)N(R3a)—, —N(R3a)C(O)NR3a—, —N(R3a)S(O)2N(R3a)—, or —OC(O)—;            R3a is hydrogen or an optionally substituted C1-4 aliphatic, and            R5 is an optionally substituted group selected from C1-6 aliphatic, 3-10-membered cycloaliphatic, 4-10-membered heterocyclyl having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur, 6-10-membered aryl, or 5-10-membered heteroaryl having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur;                        R1 is CY, —CON(R4)2, —NHCOR4, —NHSO2R4, —NHCON(R4)2, —NHCOOR4, —NHSO2N(R4)2, or —NHSO2OR4, wherein:                    CY is                        
                                     wherein:            X1, X2, and X3, are each independently N, O, S, or CR7, provided that only one of X1, X2, or X3 may be O or S,            G2 is —N═ or —NR4′—, wherein:            each occurrence of R4 or R4′ is independently H, —Z2—R6, optionally substituted C1-6 aliphatic, or optionally substituted 3-10-membered cycloaliphatic, wherein:                            Z2 is selected from an optionally substituted C1-3 alkylene chain, —S(O)—, —S(O)2—, —C(O)—, —CO2—, —C(O)NR4a—, or —S(O)2NR4a—.                R4a is hydrogen or an optionally substituted C1-4 aliphatic, and                R6 is an optionally substituted group selected from C1-6 aliphatic, 3-10-membered cycloaliphatic, 4-10-membered heterocyclyl having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur, 6-10-membered aryl, or 5-10-membered heteroaryl having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur;                                    each occurrence of R7 is independently hydrogen, —CN, halogen, —Z3—R8, C1-6 aliphatic, or 3-10-membered cycloaliphatic, wherein:                            Z3 is selected from an optionally substituted C1-3 alkylene chain, —O—, —N(R7a)—, —S—, —S(O)—, —S(O)2—, —C(O)—, —CO2—, —C(O)NR2a—, —N(R2a)C(O)—, —N(R7a)CO2—, —S(O)2NR7a—, —N(R7a)S(O)2—, —OC(O)N(R7a)—, —N(R2a)C(O)NR7a—, —N(R7a)S(O)2N(R7a)—, or —OC(O)—.                R7a is hydrogen or an optionally substituted C1-4 aliphatic, and                R8 is an optionally substituted group selected from C1-6 aliphatic, 3-10-membered cycloaliphatic, 4-10-membered heterocyclyl having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur, 6-10-membered aryl, or 5-10-membered heteroaryl having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur,                                                R2 is halogen, —W—R9, or —R9, wherein:                    W is selected from an optionally substituted C1-3 alkylene chain, —O—, —N(R2a)—, —S—, —S(O)—, —S(O)2—, —C(O)—, —CO2—, —C(O)NR2a—, —N(R2a)C(O)—, —N(R2a)CO2—, —S(O)2NR2a—, —N(R2a)S(O)2—, —OC(O)N(R2a)—, —N(R2a)C(O)NR2a—, —N(R2a)S(O)2N(R2a)—, or —OC(O)—.            R2a is hydrogen or an optionally substituted C1-4 aliphatic, and                        R9 is an optionally substituted group selected from C1-6 aliphatic, 3-10-membered cycloaliphatic, 4-10-membered heterocyclyl having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur, 6-10-membered aryl, or 5-10-membered heteroaryl having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur; and        HY is an optionally substituted nitrogen-containing heteroaryl group, provided that the optionally substituted nitrogen-containing heteroaryl group is a group other than a 3-isoxazolyl, a 2-pyridyl, a 3-pyridyl, a 5-pyrimidinyl, a 2-pyrimidinyl, a 5,6-dimethoxy-1H-benzimidazole group, or a pyrazinyl group,                    provided that:                        i) when R1 is an optionally substituted thiazolyl group and HY is an optionally substituted thiazolyl group, then the optionally substituted thiazolyl group for HY is a group represented by        
                wherein Ra is a hydrogen atom, an alkyl group or a halogen atom,        Rb is (i) a hydrogen atom, (ii) an optionally substituted hydrocarbon-carbonyl group, (iii) an optionally substituted heterocyclyl-carbonyl group, (iv) an optionally substituted carbamoyl group, (v) an optionally substituted alkoxycarbonyl group, (vi) an optionally substituted hydrocarbon-sulfonyl group, (vii) an optionally substituted heterocyclyl-sulfonyl group, (viii) an optionally substituted sulfamoyl group, (ix) an optionally substituted hydrocarbon group or (x) an optionally substituted heterocyclic group, or a salt thereof(excluding        
                ii) for compounds of formula I-B the compound is other than: 4-Thiazolecarboxamide, 2-(4-acetyl-5-methyl-1H-1,2,3-triazol-1-yl)-N,N-diethyl-5-phenyl-; 1H-1,2,3-Triazole-4-acetic acid, 1-[4-[(diethylamino)carbonyl]-5-phenyl-2-thiazolyl]-5-methyl-a-oxo-, ethyl ester; 4-Thiazolecarboxamide, 2-[4-(1,2-dioxopropyl)-5-methyl-1H-1,2,3-triazol-1-yl]-N,N-diethyl-5-phenyl-; and        provided that for compounds of formula I-B, when G1 is N, R1 is optionally substituted 1H-indazol-3-yl and R3 is CON(R4)2, then R2 is a group other than unsubstituted phenyl or 3-pyridyl;        iii) for compounds of formula I-A, where G1 is CR4,                    a) when R1 is —CON(R4)2, then R2 is an optionally substituted group selected from 6-10-membered aryl, or 5-10-membered heteroaryl having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur; and            b) the compound is other than 4-[5-[3-(2-chloro-6-fluorophenyl)-1-methyl-1H-1,2,4-triazol-5-yl]-4-methyl-2-thienyl]-pyridine; or 4-[5-(2H-tetrazol-5-yl)-2-thienyl]-pyridine;                        i. for compounds of formula I-A when R1 is —CON(R4)2, then R2 is an optionally substituted group selected from 6-10-membered aryl, or 5-10-membered heteroaryl having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur, provided that compounds are other than: 2-thiophenecarboxamide, 5-dibenz[b,f][1,4]oxazepin-11-yl-N-hydroxy-3-phenyl-; 5-Thiazolecarboxamide, 2-(3,4-dihydro-1(2H)-quinolinyl)-N-hydroxy-4-phenyl-; 5-Thiazolecarboxamide, N-hydroxy-4-phenyl-2-(4-pyridinyl)-; 5-Thiazolecarboxamide, N-[2′-(aminosulfonyl)[1,1′-biphenyl]-2-yl]-4-(4-methoxyphenyl)-2-(1H-pyrrol-1-yl)-; 5-Thiazolecarboxamide, 4-(4-nitrophenyl)-2-(4-pyridinyl)-N-(3-trifluoromethyl)phenyl]-; 5-Thiazolecarboxamide, 4-(4-bromophenyl)-N-(1-methylethyl)-2-(2-propyl-4-pyridinyl)-; 5-Thiazolecarboxamide, 2-(2,3-dihydro-1H-indol-1-yl)-4-phenyl-N-(phenylmethyl)-; 5-Thiazolecarboxamide, 2-(2,3-dihydro-4H-1,4-benzoxazin-4-yl)-4-phenyl-N-(phenylmethyl)-; 5-Thiazolecarboxamide, 4-phenyl-N-[(1S,2S)-2-(phenylmethoxy)cyclopentyl]-2-(1H-pyrazol-1-yl)-; 5-Thiazolecarboxamide, 4-phenyl-N-(phenylmethyl)-2-(1H-pyrazol-1-yl)-; 5-Thiazolecarboxamide, N-[(4-chlorophenyl)methyl]-2-(3-methoxy-1H-pyrazol-1-yl)-4-phenyl-; 5-Thiazolecarboxamide, 4-phenyl-N-[1-(phenylmethyl)-3-pyrrolidinyl]-2-(1H-pyrazol-1-yl)-; 5-Thiazolecarboxamide, 2-(1H-benzimidazol-1-yl)-4-phenyl-; 5-Thiazolecarboxamide, N-[(1S,2R)-1-[(3,5-difluorophenyl)methyl]-3-[1-(3-ethynylphenyl)cyclopropyl]amino]-2-hydroxypropyl]-4-phenyl-2-(1H-pyrrol-1-yl)-; 4-Thiazolecarboxamide, 2-(4-acetyl)-5-methyl-1H-1,2,3-triazol-1-yl)-N,N-diethyl-5-phenyl-; 3-Thiophenecarboxamide, N-[1-(aminoethyl)-2-phenylethyl]-2-(3-furanyl)-5-(1-methyl-1H-pyrazol-5-yl)-, hydrochloride; 3-Thiophenecarboxamide, N-[1-(aminoethyl)-2-phenylethyl]-2-(3-furanyl)-5-(1-methyl-1H-pyrazol-5-yl)-; Carbamic acid, N-[2-[[[2-(3-furanyl)-5-(1-methyl-1H-pyrazol-5-yl)-3-thienyl]carbonyl]amino-3-phenylpropyl]-, 1,1-dimethylethylester; 3-Thiophenecarboxamide, N-methyl,2,5-di-4-pyridinyl-; 3-Thiophenecarboxamide, 2,5-di-4-pyridinyl-; 1H-1,2,3-triazole-4-acetic acid, 1-[4-[(diethylamino)carbonyl]-5-phenyl-2-thiazolyl]-5-methyl-a-oxo-, ethyl ester; 4-Thiazolecarboxamide, 2-[4-(1,2-dioxopropyl)-5-methyl-1H-1,2,3-triazol-1-yl]-N,N-diethyl-5-phenyl-; and for compounds of formula I-B, when G1 is N, R2 is substituted or unsubstituted phenyl or pyridyl, and HY is substituted or unsubstituted 1H-indazol-3-yl, then R1 is other than CON(R4)2;        for compounds of formula I-A or I-B compounds are other than: 3-thiophenecarboxylic acid-2-(acetylamino)-5-[7-(4-chlorophenyl)-1,7-dihydro-2-(trifluoromethyl) [1,2,4]triazolo[1,5-a]pyrimidin-5-yl]-4-methyl-ethyl ester; 3-thiophenecarboxylic acid-2-(acetylamino)-5-[7-(4-chlorophenyl)-1,7-dihydro-2-(trifluoromethyl) [1,2,4]triazolo[1,5-a]pyrimidin-5-yl]-4-methyl-, ethyl ester; 5-Thiazoleacetamide, N-[[(2S)-4-[(3,4-difluorophenyl)methyl]-2-morpholinyl]methyl]-4-methyl-2-(5-methyl-3-isoxazolyl)-; 5-Thiazoleacetamide, N-[[(2S)-4-[(3,4-dichlorophenyl)methyl]-2-morpholinyl]methyl]-4-methyl-2-(5-methyl-3-isoxazolyl)-; Benzenecarboximidamide, 4-chloro-N-[[[[4-methyl-2-(2-thienyl)-5-thiazolyl]amino]carbonyl]oxy]-; Benzenecarboximidamide, N-[[[[4-methyl-2-(2-thienyl)-5-thiazolyl]amino]carbonyl]oxy]-4-(trifluoromethyl)-; Benzenecarboximidamide, dimethylethyl)-N-[[[[4-methyl-2-(2-thienyl)-5-thiazolyl]amino]carbonyl]oxy]-; Urea, N-(4-chlorophenyl)-N′-[4-methyl-2-(2-thienyl)-5-thiazolyl]-; or Urea, N-[4-(1-methylethyl)phenyl]-N′-[4-methyl-2-(2-thienyl)-5-thiazolyl]-;        v) for compounds of formula I-A or I-B:                    a) when R1 is NHCOR4, G1 is CR3, and R2 or R3 is Br, then HY is other than an optionally substituted 1H-pyrrolo[2,3-b]pyridin-4-yl group; when G1 is CR3, R1 is —NHCOR4, and R2 or R3 is CONH2, then HY is other than an optionally substituted 4,5,6,7-tetrahydro-1H-indol-1-yl or 4,5,6,7-tetrahydro-1H-indazol-1-yl group when R1 is NHCOR4, G1 is CR3, and R2 or R3 is Me, then HY is other than an optionally substituted group selected from:                        
                                     wherein ring A is an optionally substituted fused thiadiazin-3-yl, thiadiazol-3-yl, or benzo group;            b) compounds are other than those compounds where R1 or R2 is Br, R1 is —NHCOR4, and HY is optionally substituted 1H-pyrrolo[2,3-b]pyridine-4-yl;            c) compounds are other than 1H-Benzimidazole, 2,2′-[benzo[1,2-b:5,4-b]dithiophene-2,6-diylbis(4-hexyl-5,2-thiophenediyl)]bis-; Imidazo[1,2-b]pyridazine, 8-(1-ethylpropyl)-2,6-dimethyl-3-[3-methyl-5-(2H-tetrazol-5-yl)-2-thienyl;            d) compounds are other than those compounds where R1 is —NHCON(R4)2, —NHCOR4, or NHCOOR4, and R2 is —CN, —COOR9, OR9, or —CONR2aR9;            e) compounds are other than: Acetamide, N-[5-(1H-benzotriazol-1-yl)-3-cyano-4-methyl-2-thienyl]-;            f) compounds are other than: 2-Butenoic acid, 4-[[4-amino-5-(2-benzothiazolyl)-3-cyano-2-thienyl]amino]-4-oxo-; or 3-Thiophenecarboxylic acid, 4-amino-5-(2-benzothiazolyl)-2-[(3-carboxy-1-oxo-2-propen-1-yl)amino]-, 3-ethyl ester; 2-Butenoic acid, 4-[[4-amino-5-(2-benzothiazolyl)-3-cyano-2-thienyl]amino]-4-oxo-; 3-Thiophenecarboxylic acid, 4-amino-5-(2-benzothiazolyl)-2-[(3-carboxy-1-oxo-2-propen-1-yl)amino]-, 3-ethyl ester;            g) compounds are other than: -Benzimidazole, 2,2′-(3,4-dimethyl-2,5-thiophenediyl)bis[5-butoxy-4,6-dichloro-; 1H-Benzimidazole-6-carbonitrile, 2-[5-(6-dodecyl-1H-benzimidazol-2-yl)-3,4-diethoxy-2-thienyl]-; or 1H-Benzimidazole, 2,2′-[3,4-bis(phenylmethyl)-2,5-thiophenediyl]bis[5-(phenylmethyl)-;            h) compounds are other than 7H-Pyrrolo[2,3-d]pyrimidin-2-amine, 4-[4-methyl-5-(2H-tetrazol-5-yl)-2-thienyl]-N-[4-[2-(1-pyrrolidinyl)ethoxy]phenyl]-;            i) compounds are other than: Thiophene, 2,5-bis(2-benzimidazolyl)-3,4-dibromo-;            j) compounds are other than: Tricyclo[3.3.1.13,7]decane-1-carboxamide, N-[3-[2-(dimethylamino)-1-hydroxyethyl]-5-(8-quinolinyl)-2-thienyl]-; or Tricyclo[3.3.1.13,7]decane-1-carboxamide, N-[3-[2-(dimethylamino)acetyl]-5-(8-quinolinyl)-2-thienyl]-;            k) Thiophene, 2,5-bis(2-benzimidazolyl)-3,4-dibromo-; and            l) compounds are other than: Acetemide, N-[5-(4-acetyl-5-[4-[(2,4-dichlorophenyl)methoxy]-3-methoxyphenyl]-4,5-dihydro-1,3,4-oxadiazol-2-yl]-3-cyano-4-methyl-2-thienyl]-; Butanamide, N-[3-cyano-5-[3-[(2,4-dichlorophenyl)methyl]-1,2,4-oxadiazol-5-yl]-4-methyl-2-thienyl]-2-ethyl-; Acetamide, 2-bromo-N-[3-(2-chlorobenzoyl)-5-(4,5-dihydro-4,4-dimethyl-2-oxazolyl)-2-thienyl; and Acetamide, 2-amino-N-[3-(2-chlorobenzoyl)-5-(4,5-dihydro-4,4-dimethyl-2-oxazolyl)-2-thienyl]-.                        
In some embodiments of the invention, for compounds (I-A) or (I-B) or subsets thereof, R1 is CY, and CY is

In other embodiments, R1 is —CON(R4)2, —NHCOR4, —NHSO2R4, —NHCON(R4)2, —NHCOOR4, —NHSO2N(R4)2, or —NHSO2OR4.
In some embodiments, for compounds (I-A) or (I-B), or subsets thereof, HY is selected from:

wherein R10 is R10b, —V1—R10c, -T1-R10b, or —V1-T1-R10b wherein:                V1 is —NR10a—, —NR10a—C(O)—, —NR10a—C(S)—, —NR10a—C(NR10a)—, NR10aC(O)OR10a—, NR10aC(O)NR10a—, NR1aC(O)R10a—, NR1aC(S)OR10a—, NR10aC(S)NR10a—, NR10aC(S)R10a—, —NR10aC(NR10a)OR10a—, —NR10aC(NR10a)NR10a—, —NR10aS(O)2, —NR10aS(O)2NR10a—, —C(O)—, —CO2—, —C(O)NR10a—, C(O)NR10aO—, —SO2—, or —SO2N10a—;        each occurrence of R10a is independently hydrogen or an optionally substituted group selected from C1-6aliphatic, 3-10-membered cycloaliphatic, 4-10-membered heterocyclyl having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur, 6-10-membered aryl, or 5-10-membered heteroaryl having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur;        T1 is an optionally substituted C1-C6 alkylene chain wherein the alkylene chain optionally is interrupted by —N(R10a)—, —O—, —S—, —S(O)—, —S(O)2—, —C(O)—, —C(O)O—, —C(O)N(R10a)—, —S(O)2N(R10a)—, —OC(O)N(R10a)—, —N(R10a)C(O)—, —N(R10a)SO2—, —N(R10a)C(O)—, —NR10aC(O)N(R10a)—, —N(R10a)S(O)2N(R10a)—, —OC(O)—, or —C(O)N(R10a)—O— or wherein T1 forms part of an optionally substituted 3-7 membered cycloaliphatic or heterocyclyl ring;        each occurrence of R10b is independently hydrogen, halogen, —CN, —NO2, —N(R10a)2, —OR10a, —SR10a, —S(O)2R10a, —C(O)OR10a, —C(O)N(R10a)2, —S(O)2N(R10a)2, —OC(O)N(R10a)2, —N(R10a)C(O)R10a, —N(R10a)SO2R10a, —N(R10a)C(O)OR10a, —N(R10a)C(O)N(R10a)2, or —N(R10a)SO2N(R10a)2, or an optionally substituted group selected from 3-10-membered cycloaliphatic, 4-10-membered heterocyclyl having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur, 6-10-membered aryl, or 5-10-membered heteroaryl having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur;        each occurrence of R10c is independently hydrogen or an optionally substituted group selected from C1-6 aliphatic, 3-10-membered cycloaliphatic, 4-10-membered heterocyclyl having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur, 6-10-membered aryl, or 5-10-membered heteroaryl having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or        R10a and R10c taken together with a nitrogen atom to which they are bound form an optionally substituted 4-7-membered heterocyclyl ring having 0-1 additional heteroatoms independently selected from nitrogen, oxygen, or sulfur,                    wherein each occurrence of X4, X5, and X6 is independently N or CR10,            or two adjacent groups selected from Y, R11, R10, X4, X5, and X6, taken together, form an optionally substituted group selected from 3-10-membered cycloaliphatic, 4-10-membered heterocyclyl having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur, 6-10-membered aryl, or 5-10-membered heteroaryl having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur, and            each occurrence of R11 is independently hydrogen, —C(O)R11a—, —CO2R11a—, —C(O)NR11a—, C(O)NR11aO—, —SO2R11a—, —SO2NR11a—, or an optionally substituted group selected from C1-6aliphatic, 3-10-membered cycloaliphatic, 4-10-membered heterocyclyl having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur, 6-10-membered aryl, or 5-10-membered heteroaryl having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur;            wherein each occurrence of R11a is independently hydrogen or an optionally substituted group selected from C1-6aliphatic, 3-10-membered cycloaliphatic, 4-10-membered heterocyclyl having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur, 6-10-membered aryl, or 5-10-membered heteroaryl having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur; and                        Y is N or CR10.        
In other embodiments, for compounds (I-A) or (I-B), or subsets thereof, HY is selected from:
                wherein each HY group is optionally additionally substituted with one or more occurrences of R10.        
In still other embodiments, for compounds (I-A) or (I-B), or subsets thereof, HY is selected from:
                wherein each HY group is optionally additionally substituted with one or more occurrences of R10         
In still other embodiments, for compounds (I-A) or (I-B), or subsets thereof, HY is selected from:
                wherein each HY group is optionally additionally substituted with one or more occurrences of R10.        
In yet other embodiments, for compounds (I-A) or (I-B), or subsets thereof, HY is selected from:
                wherein each HY group is optionally additionally substituted with one or more occurrences of R10.        
In yet other embodiments, for compounds (I-A) or (I-B), or subsets thereof, HY is selected from:
                wherein each HY group is optionally additionally substituted with one or more occurrences of R10.        
In yet other embodiments, for compounds (I-A) or (I-B), or subsets thereof, HY is selected from:
                wherein each HY group is optionally additionally substituted with one or more occurrences of R10.        
In some embodiments, for compounds (I-A) or (I-B), or subsets thereof, G1 is CR3. In certain embodiments, G1 is CH.
In other embodiments, for compounds (I-A) or (I-B), or subsets thereof, G1 is N.
In still other embodiments, for compounds (I-A) or (I-B), or subsets thereof, R2 is a 3-10-membered cycloaliphatic, 4-10-membered heterocyclyl having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur 6-10-membered aryl, or 5-10-membered heteroaryl having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur, optionally substituted with 1-4 independent occurrences of R12, wherein R12 is —R12a, -T2-R12d, or —V2-T2-R12d, and:                each occurrence of R9a is independently halogen, —CN, —NO2, —R12c, —N(R12b)2, —OR12b, —SR12c, —S(O)2R12c, —C(O)R12b, —C(O)OR12b, —C(O)N(R12b)2, —S(O)2N(R12b)2, —OC(O)N(R12b)2, —N(R12e)C(O)R12b, —N(R12e)SO2R12c, —N(R12e)C(O)OR12b, —N(R12e)C(O)N(R12)2, or —N(R12e)SO2N(R12b)2, or two occurrences of R12b, taken together with a nitrogen atom to which they are bound, form an optionally substituted 4-7-membered heterocyclyl ring having 0-1 additional heteroatoms selected from nitrogen, oxygen, or sulfur;                    each occurrence of R12b is independently hydrogen or an optionally substituted group selected from C1-C6 aliphatic, 3-10-membered cycloaliphatic, 4-10-membered heterocyclyl having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur, 6-10-membered aryl, or 5-10-membered heteroaryl having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur;            each occurrence of R12c is independently an optionally substituted group selected from C1-C6 aliphatic, 3-10-membered cycloaliphatic, 4-10-membered heterocyclyl having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur, 6-10-membered aryl, or 5-10-membered heteroaryl having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur;            each occurrence of R12d is independently hydrogen or an optionally substituted from 3-10-membered cycloaliphatic, 4-10-membered heterocyclyl having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur, 6-10-membered aryl, or 5-10-membered heteroaryl having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur;            each occurrence of R12e is independently hydrogen or an optionally substituted C1-6 aliphatic group;            each occurrence of V2 is independently —N(R12e)—, —O—, —S—, —S(O)—, —S(O)2—, —C(O)—, —C(O)O—, —C(O)N(R12e)—, —S(O)2N(R12e)—, —OC(O)N(R12e)—, —N(R12e)C(O)—, —N(R12e)SO2—, —N(R12e)C(O)O—, —NR12eC(O)N(R12e)—, —N(R12e)SO2N(R12e)—, —OC(O)—, or —C(O)N(R12e)—O—; and            T2 is an optionally substituted C1-C6 alkylene chain wherein the alkylene chain optionally is interrupted by —N(R13)—, —O—, —S—, —S(O)—, —S(O)2—, —C(O)—, —C(O)O—, —C(O)N(R13)—, —S(O)2N(R13)—, —OC(O)N(R13)—, —N(R13)C(O)—, —N(R13)SO2—, —N(R13)C(O)O—, —NR13C(O)N(R13)—, —N(R13)S(O)2N(R13)—, —OC(O)—, or —C(O)N(R13)—O— or wherein T3 or a portion thereof optionally forms part of an optionally substituted 3-7 membered cycloaliphatic or heterocyclyl ring, wherein R13 is hydrogen or an optionally substituted C1-4aliphatic group.                        
In still other embodiments, for compounds (I-A) or (I-B), or subsets thereof, R2 is an optionally substituted 6-10-membered aryl or 5-10-membered heteroaryl having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur.
In still other embodiments, for compounds (I-A) or (I-B), or subsets thereof, R2 is a phenyl group substituted with 1-3 independent occurrences of halo, C1-3 alkyl, CN, C1-3haloalkyl, —OC1-3 alkyl, —OC1-3 haloalkyl, —NHC(O)C1-3 alkyl, —NHC(O)NHC1-3 alkyl, NHS(O)2C1-3 alkyl, or —C(O)H. In certain embodiments, R2 is a phenyl group substituted with a halogen.
In yet other embodiments, for compounds (I-A) or (I-B), or subsets thereof, R1 is CY, X1 is N, G2 is NR4′, and X2 and X3 are CR7. In certain embodiments, X3 is CH.
In still other embodiments, for compounds (I-A) or (I-B), or subsets thereof, R1 is CY, X1 and X2 are N, G2 is NR4′ and X3 is CR7. In certain embodiments, R1 is H or NH2.
In yet other embodiments, for compounds (I-A) or (I-B), or subsets thereof, wherein one or more, or all, of R1, R2 and HY are selected from:                a. R1 is CY, and CY is        
                b. R2 is a 3-10-membered cycloaliphatic, 4-10-membered heterocyclyl having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur 6-10-membered aryl, or 5-10-membered heteroaryl having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur, optionally substituted with 1-4 independent occurrences of R12, wherein R12 is —R12a, -T2-R12d, or —V2-T2-R12d, and:                    each occurrence of R9a is independently halogen, —CN, —NO2, —R12c, —N(R12b)2, —OR12b, —SR12c, —S(O)2R12c, —C(O)R12b, —C(O)OR12b, —C(O)N(R12)2, —S(O)2N(R12)2, —OC(O)N(R12)2, —N(R12e)C(O)R12b, —N(R12e)SO2R12c, —N(R12e)C(O)OR12b, —N(R12e)C(O)N(R12)2, or —N(R12e)SO2N(R12b)2, or two occurrences of R12b, taken together with a nitrogen atom to which they are bound, form an optionally substituted 4-7-membered heterocyclyl ring having 0-1 additional heteroatoms selected from nitrogen, oxygen, or sulfur;            each occurrence of R12b is independently hydrogen or an optionally substituted group selected from C1-C6aliphatic, 3-10-membered cycloaliphatic, 4-10-membered heterocyclyl having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur, 6-10-membered aryl, or 5-10-membered heteroaryl having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur;            each occurrence of R12c is independently an optionally substituted group selected from C1-C6 aliphatic, 3-10-membered cycloaliphatic, 4-10-membered heterocyclyl having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur, 6-10-membered aryl, or 5-10-membered heteroaryl having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur;            each occurrence of R12d is independently hydrogen or an optionally substituted from 3-10-membered cycloaliphatic, 4-10-membered heterocyclyl having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur, 6-10-membered aryl, or 5-10-membered heteroaryl having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur;            each occurrence of R12e is independently hydrogen or an optionally substituted C1-6 aliphatic group;            each occurrence of V2 is independently —N(R12e)—, —O—, —S—, —S(O)—, —S(O)2—, —C(O)—, —C(O)O—, —C(O)N(R12e)—, —S(O)2N(R12e)—, —OC(O)N(R12e)—, —N(R12e)C(O)—, —N(R12e)SO2—, —N(R12e)C(O)O—, —NR12eC(O)N(R12e)—, —N(R12e)SO2N(R12e)—, —OC(O)—, or —C(O)N(R12e)—O—; and            T2 is an optionally substituted C1-C6 alkylene chain wherein the alkylene chain optionally is interrupted by —N(R13)—, —O—, —S—, —S(O)—, —S(O)2—, —C(O)—, —C(O)O—, —C(O)N(R13)—, —S(O)2N(R13)—, —OC(O)N(R13)—, —N(R13)C(O)—, —N(R13)SO2—, —N(R13)C(O)O—, —NR13C(O)N(R13)—, —N(R13)S(O)2N(R13)—, —OC(O)—, or —C(O)N(R13)—O— or wherein T3 or a portion thereof optionally forms part of an optionally substituted 3-7 membered cycloaliphatic or heterocyclyl ring, wherein R13 is hydrogen or an optionally substituted C1-4aliphatic group; and                        c. HY is selected from:        
                wherein R10 is —R10b, —V1—R10c, -T1-R10b, or —V1-T1-R10b wherein:                    V1 is —NR10a—, —NR10a—C(O)—, —NR10a—C(S)—, —NR10a—C(NR10a)—, NR10aC(O)OR10a—, NR10aC(O)NR10a—, NR1aC(O)SR10a—, NR1aC(S)OR10a—, NR10aC(S)NR10a—, NR10aC(S)SR10a—, —NR10aC(NR10a)OR10a—, —NR10aC(NR10a)NR10a—, —NR10aS(O)2—, —NR10aS(O)2NR10a—, —C(O)—, —CO2—, —C(O)NR10a—, C(O)NR10aO—, —SO2—, or —SO2NR10a—;            each occurrence of R10a is independently hydrogen or an optionally substituted group selected from C1-6aliphatic, 3-10-membered cycloaliphatic, 4-10-membered heterocyclyl having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur, 6-10-membered aryl, or 5-10-membered heteroaryl having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur;            T1 is an optionally substituted C1-C6 alkylene chain wherein the alkylene chain optionally is interrupted by —N(R10a)—, —O—, —S—, —S(O)—, —S(O)2—, —C(O)—, —C(O)O—, —C(O)N(R10a)—, —S(O)2N(R10a)—, —OC(O)N(R10a)—, —N(R10a)C(O)—, —N(R10a)SO2—, —N(R10a)C(O)O—, —NR10aC(O)N(R10a)—, —N(R10a)S(O)2N(R10a)—, —OC(O)—, or —C(O)N(R10a)—O— or wherein T1 forms part of an optionally substituted 3-7 membered cycloaliphatic or heterocyclyl ring;            each occurrence of R10b is independently hydrogen, halogen, —CN, —NO2, —N(R10a)2, —SR10a, —S(O)2R10a, —C(O)R10a, —C(O)OR10a, —C(O)N(R10a)2, —S(O)2N(R10a)2, —OC(O)N(R10a)2, —N(R10a)C(O)R10a, —N(R10a)SO2R10a, —N(R10a)C(O)OR10a, —N(R10a)C(O)N(R10a)2, or —N(R10a)SO2N(R10a)2, or an optionally substituted group selected from 3-10-membered cycloaliphatic, 4-10-membered heterocyclyl having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur, 6-10-membered aryl, or 5-10-membered heteroaryl having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur;            each occurrence of R10c is independently hydrogen or an optionally substituted group selected from C1-6 aliphatic, 3-10-membered cycloaliphatic, 4-10-membered heterocyclyl having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur, 6-10-membered aryl, or 5-10-membered heteroaryl having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or            R10a and R10c taken together with a nitrogen atom to which they are bound form an optionally substituted 4-7-membered heterocyclyl ring having 0-1 additional heteroatoms independently selected from nitrogen, oxygen, or sulfur,            wherein each occurrence of X4, X5, and X6 is independently N or CR10,            or two adjacent groups selected from Y, R11, R10, X4, X5, and X6, taken together, form an optionally substituted group selected from 3-10-membered cycloaliphatic, 4-10-membered heterocyclyl having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur, 6-10-membered aryl, or 5-10-membered heteroaryl having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur, and            each occurrence of R11 is independently hydrogen, —C(O)R11a—, —CO2R11a—, —C(O)NR11a—, C(O)NR11aO—, —SO2R11a—, —SO2NR11a—, or an optionally substituted group selected from C1-6aliphatic, 3-10-membered cycloaliphatic, 4-10-membered heterocyclyl having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur, 6-10-membered aryl, or 5-10-membered heteroaryl having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur;            wherein each occurrence of R11a is independently hydrogen or an optionally substituted group selected from C1-6aliphatic, 3-10-membered cycloaliphatic, 4-10-membered heterocyclyl having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur, 6-10-membered aryl, or 5-10-membered heteroaryl having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur; and                        Y is N or CR10.        
In yet other embodiments, for compounds (I-A), or subsets thereof, G1 is CR3, HY is an optionally substituted 6-membered nitrogen-containing heteroaryl group, and R1 is —NHCOR4, —NHSO2R4, —NHCON(R4)2, —NHCOOR4, —NHSO2N(R4)2, or —NHSO2OR4.
In certain embodiments, G1 is CH;                HY is        
                 xviii;        R1 is —NHCOR4, —NHSO2R4, —NHCON(R4)2, —NHCOOR4, —NHSO2N(R4)2, or —NHSO2OR4,        R4 is C1-6 alkyl, and        R2 is a C6-18 aryl group which is optionally substituted by halogen.        
In other embodiments:                G1 is CH;        HY is        
                 xviii, wherein                    R11 is C1-6 arkylcarbonyl,            R1 is —NHCOR4, R4 is C1-6 alkyl and            R2 is a C6-18 aryl group which is optionally substituted by halogen.                        
In still other embodiments, for compounds (I-A) or (I-B), or subsets thereof G1 is CR3, HY is an optionally substituted bicyclic or polycyclic nitrogen-containing heteroaryl group, and R1 is CY, —CON(R4)2, —NHCOR4, —NHSO2R4, —NHCON(R4)2, —NHCOOR4, —NHSO2N(R4)2, or —NHSO2OR4.
In yet other embodiments, for compounds of formula (I-A) or (I-B), wherein G1 is N, HY is an optionally substituted nitrogen-containing heteroaryl group, and R1 is, —NHCOR4, —NHSO2R4, —NHCON(R4)2, —NHCOOR4, —NHSO2N(R4)2, or —NHSO2OR4.
In other embodiments, compounds of formula (I-B) are provided where G1 is CH.
In certain other embodiments, R1 is CY, and CY is
R2 is an optionally substituted 6-10-membered aryl or 5-10-membered heteroaryl having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur.
In yet other embodiments, R2 is a phenyl group substituted with 1-3 independent occurrences of halo, C1-3 alkyl, CN, C1-3haloalkyl, —OC1-3 alkyl, —OC1-3 haloalkyl, —NHC(O)C1-3 alkyl, —NHC(O)NHC1-3 alkyl, NHS(O)2C1-3 alkyl, or —C(O)H.
In still other embodiments, X1 is N and X2 and X3 are CH. In yet other embodiments, X1 and X2 are N, and X3 is CH.
In still other embodiments, a compound of formula II-A-I is provided:
                wherein R10d is hydrogen or optionally substituted C1-4alkyl, and R10e is R10.        
In some embodiments, for compound II-A-i, R10e is —V1—R10c, or halogen. In other embodiments, for compound II-A-i, X1 is N and X2 and X3 are H. In other embodiments, X1 and X2 are N, and X3 is H.
In still other embodiments for compound II-A-i, R2 is an optionally substituted 6-10-membered aryl or 5-10-membered heteroaryl having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur.
In yet other embodiments, for compound II-A-i, R2 is a phenyl group substituted with 1-3 independent occurrences of halo, C1-3 alkyl, CN, C1-3haloalkyl, —OC1-3 alkyl, —OC1-3 haloalkyl, —NHC(O)C1-3 alkyl, —NHC(O)NHC1-3 alkyl, NHS(O)2C1-3 alkyl, or —C(O)H.
In yet other embodiments, a compound of formula IA or IB is provided:
or a pharmaceutically acceptable salt thereof, wherein:                G1 is N or CR3, wherein R3 is H, —CN, halogen, —Z—R5, C1-6 aliphatic, or 3-10-membered cycloaliphatic, wherein:                    Z is selected from an optionally substituted C1-3 alkylene chain, —O—, —N(R3a)—, —S—, —S(O)—, —S(O)2—, —C(O)—, —CO2—, —C(O)NR3a—, —N(R3a)C(O)—, —N(R3a)CO2—, —S(O)2NR3a—, —N(R3a)S(O)2—, —OC(O)N(R3a)—, —N(R3a)C(O)NR3a—, —N(R3a)S(O)2N(R3a)—, or —OC(O)—;            R3a is hydrogen or an optionally substituted C1-4 aliphatic, and            R5 is an optionally substituted group selected from C1-6 aliphatic, 3-10-membered cycloaliphatic, 4-10-membered heterocyclyl having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur, 6-10-membered aryl, or 5-10-membered heteroaryl having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur;                        R1 is CY, —CON(R4)2, —NHCOR4, —NHSO2R4, —NHCON(R4)2, —NHCOOR4, —NHSO2N(R4)2, or —NHSO2OR4, wherein:                    CY is                        
                                     wherein:            X1, X2, and X3, are each independently N, O, S, or CR7, provided that only one of X1, X2, or X3 may be O or S,            G2 is —N═ or —NR4′—, wherein:            each occurrence of R4 and R4′ is independently H, —Z2—R6, optionally substituted C1-6 aliphatic, or optionally substituted 3-10-membered cycloaliphatic, wherein:                            Z2 is selected from an optionally substituted C1-3 alkylene chain, —S(O)—, —S(O)2—, —C(O)—, —CO2—, —C(O)NR4a—, or —S(O)2NR4a—.                R4a is hydrogen or an optionally substituted C1-4 aliphatic, and                R6 is an optionally substituted group selected from C1-6 aliphatic, 3-10-membered cycloaliphatic, 4-10-membered heterocyclyl having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur, 6-10-membered aryl, or 5-10-membered heteroaryl having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur;                                    each occurrence of R7 is independently hydrogen, —CN, halogen, —Z3—R8, C1-6 aliphatic, or 3-10-membered cycloaliphatic, wherein:                            Z3 is selected from an optionally substituted C1-3 alkylene chain, —O—, —N(R7a)—, —S—, —S(O)—, —S(O)2—, —C(O)—, —CO2—, —C(O)NR7a—, —N(R7a)C(O)—, —N(R7a)CO2—, —S(O)2NR7a—, —N(R7a)S(O)2—, —OC(O)N(R7a)—, —N(R7a)C(O)NR7a—, —N(R7a)S(O)2N(R7a)—, or —OC(O)—.                R7a is hydrogen or an optionally substituted C1-4 aliphatic, and                R8 is an optionally substituted group selected from C1-6 aliphatic, 3-10-membered cycloaliphatic, 4-10-membered heterocyclyl having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur, 6-10-membered aryl, or 5-10-membered heteroaryl having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur,                                    R2 is halogen, —W—R9, or —R9, wherein:                            W is selected from an optionally substituted C1-3 alkylene chain, —O—, —N(R2a)—, —S—, —S(O)—, —S(O)2—, —C(O)—, —CO2—, —C(O)NR2a—, —N(R2a)C(O)—, —N(R2a)CO2—, —S(O)2NR2a—, —N(R2a)S(O)2—, —OC(O)N(R2a)—, —N(R2a)C(O)NR2a—, —N(R2a)S(O)2N(R2a)—, or —OC(O)—.                                    R2a is hydrogen or an optionally substituted C1-4 aliphatic, andR9 is an optionally substituted group selected from C1-6aliphatic, 3-10-membered cycloaliphatic, 4-10-membered heterocyclyl having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur, 6-10-membered aryl, or 5-10-membered heteroaryl having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur; and                        HY is selected from:        
                wherein each HY group is optionally additionally substituted with one or more occurrences of R10.        
In some embodiments, R1 is CY, and CY is
In other embodiments, R1 is —CON(R4)2, —NHCOR4, —NHSO2R4, —NHCON(R4)2, —NHCOOR4, —NHSO2N(R4)2, or —NHSO2OR4. In yet other embodiments, G1 is CR3. In still other embodiments, G1 is N.
In yet other embodiments, R2 is a 3-10-membered cycloaliphatic, 4-10-membered heterocyclyl having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur 6-10-membered aryl, or 5-10-membered heteroaryl having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur, optionally substituted with 1-4 independent occurrences of R12, wherein R12 is —R12a, -T2-R12d, or —V2-T2-R12d, and:                each occurrence of R9a is independently halogen, —CN, —NO2, —R12c, —N(R12b)2, —OR12b, —SR12c, —S(O)2R12c, —C(O)R12b, —C(O)OR12b, —C(O)N(R12b)2, —S(O)2N(R12)2, —OC(O)N(R12)2, —N(R12e)C(O)R12b, —N(R12e)SO2R12c, —N(R12e)C(O)OR12b, —N(R12e)C(O)N(R12b)2, or —N(R12e)SO2N(R12b)2, or two occurrences of R12b, taken together with a nitrogen atom to which they are bound, form an optionally substituted 4-7-membered heterocyclyl ring having 0-1 additional heteroatoms selected from nitrogen, oxygen, or sulfur; each occurrence of R12b is independently hydrogen or an optionally substituted group selected from C1-C6 aliphatic, 3-10-membered cycloaliphatic, 4-10-membered heterocyclyl having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur, 6-10-membered aryl, or 5-10-membered heteroaryl having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur; each occurrence of R12c is independently an optionally substituted group selected from C1-C6 aliphatic, 3-10-membered cycloaliphatic, 4-10-membered heterocyclyl having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur, 6-10-membered aryl, or 5-10-membered heteroaryl having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur;        each occurrence of R12d is independently hydrogen or an optionally substituted from 3-10-membered cycloaliphatic, 4-10-membered heterocyclyl having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur, 6-10-membered aryl, or 5-10-membered heteroaryl having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur;                    each occurrence of R12e is independently hydrogen or an optionally substituted C1-6 aliphatic group;            each occurrence of V2 is independently —N(R12e)—, —O—, —S—, —S(O)—, —S(O)2—, —C(O)—, —C(O)O—, —C(O)N(R12e)—, —S(O)2N(R12e)—, —OC(O)N(R12e)—, —N(R12e)C(O)—, —N(R12e)SO2—, —N(R12e)C(O)O—, —NR12eC(O)N(R12e)—, —N(R12e)SO2N(R12e)—, —OC(O)—, or —C(O)N(R12e)—O—; and            T2 is an optionally substituted C1-C6 alkylene chain wherein the alkylene chain optionally is interrupted by —N(R13)—, —O—, —S—, —S(O)—, —S(O)2—, —C(O)—, —C(O)O—, —C(O)N(R13)—, —S(O)2N(R13)—, —OC(O)N(R13)—, —N(R13)C(O)—, —N(R13)SO2—, —N(R13)C(O)O—, —NR13C(O)N(R13)—, —N(R13)S(O)2N(R13)—, —OC(O)—, or —C(O)N(R13)—O— or wherein T3 or a portion thereof optionally forms part of an optionally substituted 3-7 membered cycloaliphatic or heterocyclyl ring, wherein R13 is hydrogen or an optionally substituted C1-4aliphatic group.                        
In still other embodiments, R2 is an optionally substituted 6-10-membered aryl or 5-10-membered heteroaryl having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur. In yet other embodiments, R2 is a phenyl group substituted with 1-3 independent occurrences of halo, C1-3 alkyl, CN, C1-3haloalkyl, —OC1-3 alkyl, —OC1-3 haloalkyl, —NHC(O)C1-3 alkyl, —NHC(O)NHC1-3 alkyl, NHS(O)2C1-3 alkyl, or —C(O)H.
As described in the general description above, in certain embodiments, compounds of formula II-A are provided:
or a pharmaceutically acceptable salt thereof, wherein:                R1 is CY is        
                R2 is H, halogen, —W—R9, or —R9, wherein:                    W is selected from an optionally substituted C1-3 alkylene chain, —O—, —N(R2a)—, —S—, —S(O)—, —S(O)2—, —C(O)—, —CO2—, —C(O)NR2a—, —N(R2a)C(O)—, —N(R2a)CO2—, —S(O)2NR2a—, —N(R2a)S(O)2—, —OC(O)N(R2a)—, —N(R2a)C(O)NR2a—, —N(R2a)S(O)2N(R2a)—, or —OC(O)—.            R2a is hydrogen or an optionally substituted C1-4 aliphatic, and            R9 is an optionally substituted group selected from C1-6 aliphatic, 3-10-membered cycloaliphatic, 4-10-membered heterocyclyl having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur, 6-10-membered aryl, or 5-10-membered heteroaryl having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur;                        R3 is H, —CN, halogen, —Z—R5, C1-6 aliphatic, or 3-10-membered cycloaliphatic, wherein:                    Z is selected from an optionally substituted C1-3 alkylene chain, —O—, —N(R3a)—, —S—, —S(O)—, —S(O)2—, —C(O)—, —CO2—, —C(O)NR3a—, —N(R3a)C(O)—, —N(R3a)CO2—, —S(O)2NR3a—, —N(R3a)S(O)2—, —OC(O)N(R3a)—, —N(R34)C(O)NR3a—, —N(R3a)S(O)2N(R3a)—, or —OC(O)—;            R3a is hydrogen or an optionally substituted C1-4 aliphatic, and            R5 is an optionally substituted group selected from C1-6 aliphatic, 3-10-membered cycloaliphatic, 4-10-membered heterocyclyl having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur, 6-10-membered aryl, or 5-10-membered heteroaryl having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur;                        each occurrence of R4 and R4′ is independently H, —Z—R6, C1-6 aliphatic, or 3-10-membered cycloaliphatic, wherein:                    Z is selected from an optionally substituted C1-3 alkylene chain, —O—, —N(R4a)—, —S(O)—, —S(O)2—, —C(O)—, —CO2—, —C(O)NR4a—, —N(R4a)C(O)—, —N(R4a)CO2—, —S(O)2NR4a—, —N(R4a)S(O)2—, —OC(O)N(R4a)—, —N(R4a)C(O)NR4a—, —N(R4a)S(O)2N(R4a)—, or —OC(O)—.            R4a is hydrogen or an optionally substituted C1-4 aliphatic, and            R6 is an optionally substituted group selected from C1-6 aliphatic, 3-10-membered cycloaliphatic, 4-10-membered heterocyclyl having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur, 6-10-membered aryl, or 5-10-membered heteroaryl having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur; and                        X1, X2, and X3, are each independently N or CR7, wherein each occurrence of R7 is independently hydrogen, —CN, halogen, —Z3—R8, optionally substituted C1-6 aliphatic, or optionally substituted 3-10-membered cycloaliphatic, wherein:                    Z3 is selected from an optionally substituted C1-3 alkylene chain, —O—, —N(R7a)—, —S—, —S(O)—, —S(O)2—, —C(O)—, —CO2—, —C(O)NR7a—, —N(R7a)C(O)—, —N(R7a)CO2—, —S(O)2NR7a—, —N(R7a)S(O)2—, —OC(O)N(R74)—, —N(R7a)C(O)NR7a—, —N(R7a)S(O)2N(R7a)—, or —OC(O)—;            R7a is hydrogen or an optionally substituted C1-4 aliphatic, and            R8 is an optionally substituted group selected from C1-6 aliphatic, 3-10-membered cycloaliphatic, 4-10-membered heterocyclyl having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur, 6-10-membered aryl, or 5-10-membered heteroaryl having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur, and                        X4, X5 and X6 are each independently R10, wherein:        R10 is —R10b, or —V1—R10c, -T1-R10b, or —V1-T1-R10b wherein:                    V1 is —NR10a—, —NR10a—C(O)—, —NR10a—C(S)—, —NR10a—C(NR10a)—, NR10aC(O)O—, NR10aC(O)NR10a—, NR10aC(O)Sa—, NR10aC(S)O—, NR10aC(S)NR10a—, NR10aC(S)S—, —NR10aC(NR10a)O—, —NR10aC(NR10a)NR10a—, —NR10aS(O)2—, —NR10aS(O)2NR10a—, —C(O)—, —CO2—, C(O)NR10a—, —C(O)NR10aO—, —SO2—, or —SO2NR10a—;            each occurrence of R10a is independently hydrogen or an optionally substituted group selected from C1-6aliphatic, 3-10-membered cycloaliphatic, 4-10-membered heterocyclyl having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur, 6-10-membered aryl, or 5-10-membered heteroaryl having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur;            T1 is an optionally substituted C1-C6 alkylene chain wherein the alkylene chain optionally is interrupted by —N(R10a)—, —O—, —S—, —S(O)—, —S(O)2—, —C(O)—, —C(O)O—, —C(O)N(R10a)—, —S(O)2N(R10a)—, —OC(O)N(R10a)—, —N(R10a)C(O)—, —N(R10a)SO2—, —N(R10a)C(O)O—, —NR10aC(O)N(R10a)—, —N(R10a)S(O)2N(R10a)—, —OC(O)—, or —C(O)N(R10a)—O— or wherein T1 forms part of an optionally substituted 3-7 membered cycloaliphatic or heterocyclyl ring;            each occurrence of R10b is independently hydrogen, halogen, —CN, —NO2, —N(R10a)2, —SR10a, —S(O)2R10a, —C(O)R10a, —C(O)OR10a, —C(O)N(R10a)2, —S(O)2N(R10a)2, —OC(O)N(R10a)2, —N(R10a)C(O)R10a, —N(R10a)SO2R10a, —N(R10a)C(O)OR10a, —N(R10a)C(O)N(R10a)2, or —N(R10a)SO2N(R10a)2, or an optionally substituted group selected from 3-10-membered cycloaliphatic, 4-10-membered heterocyclyl having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur, 6-10-membered aryl, or 5-10-membered heteroaryl having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur;            each occurrence of R10c is independently hydrogen or an optionally substituted group selected from C1-6 aliphatic, 3-10-membered cycloaliphatic, 4-10-membered heterocyclyl having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur, 6-10-membered aryl, or 5-10-membered heteroaryl having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or            R10a and R10c taken together with a nitrogen atom to which they are bound form an optionally substituted 4-7-membered heterocyclyl ring having 0-1 additional heteroatoms independently selected from nitrogen, oxygen, or sulfur;                        provided that:        a) when R1 is —CONHR4, then R2 is an optionally substituted group selected from 6-10-membered aryl, or 5-10-membered heteroaryl having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur; and        b) the compound of formula I is other than 4-[5-[3-(2-chloro-6-fluorophenyl)-1-methyl-1H-1,2,4-triazol-5-yl]-4-methyl-2-thienyl]-pyridine; or 4-[5-(2H-tetrazol-5-yl)-2-thienyl]-pyridine.        
In certain embodiments, for compounds of general formula II-A, one or more substituents are selected from:
(a) R2 is an optionally substituted 6-10-membered aryl, or 5-10-membered heteroaryl having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur; or
(b) R10 is —V1—R10c.
In other embodiments, for compounds of general formula II-A, compounds are represented by:

In still other embodiments, for compounds of general formulas II-A, II-A-a, II-A-b, II-A-c, II-A-d, II-A-e, or II-A-f, X5 is N, and X4 and X6 are each CR10. In yet other embodiments, X4 is N, and X5 and X6 are each CR10. In still other embodiments, X4, X5 and X6 are each CR10. In further embodiments, R10 is hydrogen, halogen or a C1-6 alkyl group.
In other embodiments, for compounds of general formulas II-A, II-A-a, II-A-b, II-A-c, II-A-d, II-A-e, or II-A-f, R10 is —V1—R10c or —V1-TI-R10b wherein:                V1 is —NR10a—, —NR10aC(O)—, —NR10a—C(NR10a)—, NR10aC(O)O—, or —NR10aS(O)2—;                    each occurrence of R10a is independently hydrogen, C1-6alkyl group, or 3-10-membered cycloalkyl group;            T1 is C1-C6 alkylene chain wherein the alkylene chain optionally is interrupted by —N(R10a)—, or —O—;            each occurrence of R10b is independently hydrogen, halogen, —N(R10a)2, —N(R10a)C(O)R10a;            each occurrence of R10c is independently hydrogen, a C1-6 alkyl group optionally substituted by halogen or hydroxyl, or a 6-10-membered aryl group optionally substituted by C1-6 alkyl or C1-6 alkyloxy.                        
In other embodiments, for compounds of general formula II-A, II-A-a, II-A-b, II-A-c, II-A-d, II-A-e, or II-A-f, R2 is a 3-10-membered cycloaliphatic, 4-10-membered heterocyclyl having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur 6-10-membered aryl, or 5-10-membered heteroaryl having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur, optionally substituted with 1-4 independent occurrences of R9, wherein R9 is —R9a, -T2-R9d, or —V2-T2-R9d, and:
each occurrence of R9a is independently halogen, —CN, —NO2, —R9c, —N(R9b)2, —OR9b, —SR9c, —S(O)2R9c, —C(O)R9b, —C(O)OR9b, —C(O)N(R9b)2, —S(O)2N(R9b)2, —OC(O)N(R9b)2, —N(R9e)C(O)R9b, —N(R9e)SO2R9c, —N(R9e)C(O)OR9b, —N(R9e)C(O)N(R9b)2, or —N(R9e)SO2N(R9b)2, or two occurrences of R9b, taken together with a nitrogen atom to which they are bound, form an optionally substituted 4-7-membered heterocyclyl ring having 0-1 additional heteroatoms selected from nitrogen, oxygen, or sulfur;
each occurrence of R9b is independently hydrogen or an optionally substituted group selected from C1-C6 aliphatic, 3-10-membered cycloaliphatic, 4-10-membered heterocyclyl having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur, 6-10-membered aryl, or 5-10-membered heteroaryl having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur;
each occurrence of R9c is independently an optionally substituted group selected from C1-C6 aliphatic, 3-10-membered cycloaliphatic, 4-10-membered heterocyclyl having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur, 6-10-membered aryl, or 5-10-membered heteroaryl having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur;
each occurrence of R9d is independently hydrogen or an optionally substituted from 3-10-membered cycloaliphatic, 4-10-membered heterocyclyl having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur, 6-10-membered aryl, or 5-10-membered heteroaryl having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur;
each occurrence of R9e is independently hydrogen or an optionally substituted C1-6 aliphatic group;
each occurrence of V2 is independently —N(R9e)—, —O—, —S—, —S(O)—, —S(O)2—, —C(O)—, —C(O)O—, —C(O)N(R9e)—, —S(O)2N(R9e)—, —OC(O)N(R9e)—, —N(R9e)C(O)—, —N(R9e)SO2—, —N(R9e)C(O)O—, —NR9eC(O)N(R9e)—, —N(R9e)SO2N(R9e)—, —OC(O)—, or —C(O)N(R9e)—O—; and
T2 is an optionally substituted C1-C6 alkylene chain wherein the alkylene chain optionally is interrupted by —N(R7a)—, —O—, —S—, —S(O)—, —S(O)2—, —C(O)—, —C(O)O—, —C(O)N(R7a)—, —S(O)2N(R7a)—, —OC(O)N(R7a)—, —N(R7a)C(O)—, —N(R7a)SO2—, —N(R7a)C(O)O—, —NR7aC(O)N(R7a)—, —N(R7a)S(O)2N(R7a)—, —OC(O)—, or —C(O)N(R7a)—O— or wherein T3 or a portion thereof optionally forms part of an optionally substituted 3-7 membered cycloaliphatic or heterocyclyl ring.
In still other embodiments for compounds of general formula II-A, II-A-a, II-A-b, II-A-c, II-A-d, II-A-e, or II-A-f, R2 is a phenyl group substituted with 1-3 independent occurrences of halo, C1-3 alkyl, CN, C1-3haloalkyl, —OC1-3 alkyl, —OC1-3 haloalkyl, —NHC(O)C1-3 alkyl, —NHC(O)NHC1-3 alkyl, NHS(O)2C1-3 alkyl, or —C(O)H. In further other embodiments for compounds of general formula II-A, II-A-a, II-A-b, II-A-c, II-A-d, II-A-e, or II-A-f, R2 is a phenyl group substituted with 1-3 independent occurrences of halo.
In yet other embodiments, for compounds of general formula II-A, II-A-a, II-A-b, II-A-c, II-A-d, II-A-e, or II-A-f, and subsets thereof, R3 is H or CN.
In other embodiments, for compounds of general formula II-A, II-A-a, II-A-b, II-A-c, II-A-d, II-A-e, or II-A-f, R4 is H, or —Z—R6, wherein: Z is C1-3 alkylene chain, and R6 is a 6-10-membered aryl group.
In other embodiments, for compounds of general formula II-A, II-A-a, II-A-b, II-A-c, II-A-d, II-A-e, or II-A-f, R7 is independently hydrogen, halogen, or a C1-6 alkyl group, or —Z3—R8 wherein:                Z3 is selected from C1-3 alkylene chain, or —CO2—, and        R8 is a C1-6 alkyl group, a 4-10-membered heterocyclyl group having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or a 6-10-membered aryl group each of which is optionally substituted by halogen.        
In other embodiments, the compound has the structure of formula I-A-iii:

In some embodiments, for compounds of formula II-A, II-A-a, II-A-b, II-A-c, II-A-d, II-A-e, or II-A-f:
R10 is —V1—R10c, where V1 is —NR10aCO—, —N(R10a)2 or —NR10aC(NR10a)NR10a— and
R2 is a phenyl group substituted with 1-3 independent occurrences of halo, C1-3 alkyl, —CN, C1-3haloalkyl, —OC1-3 alkyl, —OC1-3 haloalkyl, —NHC(O)C1-3 alkyl, —NHC(O)NHC1-3 alkyl, NHS(O)2C1-3 alkyl, or —C(O)H.
Preferred R10a is independently hydrogen, a C1-6alkyl group, or a 3-10-membered cycloalkyl group, particularly hydrogen and preferred R10c is independently hydrogen, a C1-6 alkyl group optionally substituted by halogen or hydroxyl, or a 6-10-membered aryl group optionally substituted by C1-6 alkyl or C1-6 alkyloxy.
Preferred R2 is a phenyl group optionally substituted with 1-3 independent occurrences of halo.
In some embodiments for compounds of formulas II-A, II-A-a, II-A-b, II-A-c, II-A-d, II-A-e, or II-A-f, X4 is N and X5 and X6 are each CR10.
In other embodiments, for compounds of formulas II-A, II-A-a, II-A-b, II-A-c, II-A-d, II-A-e, or II-A-f, X4 is N, X5 is N, and X6 is CR10.
In other embodiments, for compounds of formulas II-A, II-A-a, II-A-b, II-A-c, II-A-d, II-A-e, or II-A-f, R10 is hydrogen, halogen or a C1-6 alkyl group.
In other embodiments, for compounds of formulas II-A, II-A-a, II-A-b, II-A-c, II-A-d, II-A-e, or II-A-f, any combination of preferable group of each symbol mentioned above is used.
In still other embodiments, as described in the general description above, the present invention provides compounds represented by the formulas (I-A-i), (I-A-ii), (II-A-ii), (I-B-i) and additional description for these compounds is provided directly below.
As the “optionally substituted group bonded via a carbon atom” in the present specification, cyano, an optionally substituted alkyl group (preferably C1-20 alkyl group, particularly preferably C1-8 alkyl group), an optionally substituted alkenyl group (preferably C2-8 alkenyl group), an optionally substituted alkynyl group (preferably C2-8 alkynyl group), an optionally substituted C1-8 alkyl-carbonyl group, an optionally substituted C3-8 cycloalkyl group, an optionally substituted aryl group (preferably C6-18 aryl group), an optionally substituted C6-18 aryl-C1-4 alkyl group, an optionally substituted C6-18 aryl-carbonyl group, an optionally substituted C6-18 aryl-C1-4 alkyl-carbonyl group, an optionally substituted heterocyclic group (heterocyclic group bonded via a carbon atom), an optionally substituted heterocyclyl-C1-4 alkyl group, an optionally substituted heterocyclyl-carbonyl group, an optionally substituted heterocyclyl-C1-4 alkyl-carbonyl group, an optionally substituted carbamoyl group and the like can be used.
Examples of the “C1-20 alkyl group” of the above-mentioned “optionally substituted C1-20 alkyl group” include C1-8 alkyl such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, 1-ethylpropyl, hexyl, isohexyl, 1,1-dimethylbutyl, 2,2-dimethylbutyl, 3,3-dimethylbutyl, 2-ethylbutyl, heptyl, octyl etc., and the like.
The “alkyl group” of the above-mentioned “optionally substituted alkyl group” may have not less than 1 (preferably 1 to 5, more preferably 1 to 3) substituents at substitutable position(s). Such substituent(s) may be one to an acceptable maximum number of substituents at any substitutable position(s), which is/are selected from a substituent group consisting of
(1) a halogen atom (e.g., fluorine, chlorine, bromine, iodine);
(2) cyano;
(3) nitro;
(4) hydroxy;
(5) C1-6 alkoxy (e.g., methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, tert-butoxy etc.) optionally having 1 to 3 substituents selected from a halogen atom (e.g., fluorine, chlorine, bromine, iodine) and C1-6 alkoxy (e.g., methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, tert-butoxy etc.);(6) C2-6 alkenyloxy (e.g., ethenyloxy, propenyloxy, butenyloxy, pentenyloxy, hexenyloxy etc.) optionally having 1 to 3 halogen atoms (e.g., fluorine, chlorine, bromine, iodine);(7) C2-6 alkynyloxy (e.g., ethynyloxy, propynyloxy, butynyloxy, pentynyloxy, hexynyloxy etc.) optionally having 1 to 3 halogen atoms (e.g., fluorine, chlorine, bromine, iodine);(8) C3-8 cycloalkyloxy (e.g., cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy) optionally having 1 to 3 halogen atoms (e.g., fluorine, chlorine, bromine, iodine);(9) C3-8 cycloalkenyloxy (e.g., cyclopropenyloxy, cyclobutenyloxy, cyclopentenyloxy, cyclohexenyloxy etc.) optionally having 1 to 3 halogen atoms (e.g., fluorine, chlorine, bromine, iodine);(10) C6-14 aryloxy (e.g., phenyloxy, 1-naphthyloxy, 2-naphthyloxy etc.) optionally having 1 to 3 halogen atoms (e.g., fluorine, chlorine, bromine, iodine);(11) C3-8 cycloalkyl-C1-6 alkoxy (e.g., cyclopropylmethyloxy, cyclopropylethyloxy, cyclobutylmethyloxy, cyclopentylmethyloxy, cyclohexylmethyloxy, cyclohexylethyloxy etc.) optionally having 1 to 3 halogen atoms (e.g., fluorine, chlorine, bromine, iodine);(12) C3-8cycloalkenyl-C1-6 alkoxy (e.g., cyclopentenylmethyloxy, cyclohexenylmethyloxy, cyclohexenylethyloxy, cyclohexenylpropyloxy etc.) optionally having 1 to 3 halogen atoms (e.g., fluorine, chlorine, bromine, iodine);(13) C6-14 aryl-C1-6alkoxy (e.g., phenylmethyloxy, phenylethyloxy etc.) optionally having 1 to 3 halogen atoms (e.g., fluorine, chlorine, bromine, iodine);(14) 4- to 7-membered (preferably 5- or 6-membered) monocyclic aromatic heterocyclyl-C1-4 alkyl-oxy containing, as a ring constituting atom besides carbon atom, 1 to 4 heteroatoms selected from an oxygen atom, a sulfur atom and a nitrogen atom;(15) 4- to 7-membered (preferably 5- or 6-membered) monocyclic non-aromatic heterocyclyl-C1-4 alkyl-oxy (e.g., morpholinylethyloxy, piperidinylethyloxy etc.) containing, as a ring constituting atom besides carbon atom, 1 to 4 heteroatoms selected from an oxygen atom, a sulfur atom and a nitrogen atom;(16) C1-6 alkyl-aminosulfonyl (e.g., methylaminosulfonyl, ethylaminosulfonyl, propylaminosulfonyl etc.);(17) di-C1-6 alkyl-aminosulfonyl (e.g., dimethylaminosulfonyl, diethylaminosulfonyl, dipropylaminosulfonyl etc.);(18) C1-6 alkyl-aminocarbonyl (e.g., methylaminocarbonyl, ethylaminocarbonyl, propylaminocarbonyl etc.);(19) di-C1-6 alkyl-aminocarbonyl (e.g., dimethylaminocarbonyl, diethylaminocarbonyl, dipropylaminocarbonyl etc.);(20) formyl;(21) C1-6 alkyl-carbonyl (e.g., acetyl, ethylcarbonyl, propylcarbonyl, isopropylcarbonyl etc.);(22) C2-6 alkenyl-carbonyl (e.g., ethenylcarbonyl, propenylcarbonyl, butenylcarbonyl, pentenylcarbonyl, hexenylcarbonyl etc.);(23) C2-6 alkynyl-carbonyl (e.g., ethynylcarbonyl, propynylcarbonyl, butynylcarbonyl, pentynylcarbonyl, hexynylcarbonyl etc.);(24) C3-8 cycloalkyl-carbonyl (e.g., cyclopropylcarbonyl, cyclobutylcarbonyl, cyclopentylcarbonyl, cyclohexylcarbonyl etc.);(25) C3-6cycloalkenyl-carbonyl (e.g., cyclopropenylcarbonyl, cyclobutenylcarbonyl, cyclopentenylcarbonyl, cyclohexenylcarbonyl etc.);(26) C6-14 aryl-carbonyl (e.g., benzoyl, 1-naphthylcarbonyl, 2-naphthylcarbonyl etc.);(27) C3-8 cycloalkyl-C1-6alkyl-carbonyl (e.g., cyclopropylmethylcarbonyl, cyclopropylethylcarbonyl, cyclobutylmethylcarbonyl, cyclopentylmethylcarbonyl, cyclohexylmethylcarbonyl, cyclohexylethylcarbonyl etc.);(28) C3-6cycloalkenyl-C1-6alkyl-carbonyl (e.g., cyclopentenylmethylcarbonyl, cyclohexenylmethylcarbonyl, cyclohexenylethylcarbonyl, cyclohexenylpropylcarbonyl etc.);(29) C6-14aryl-C1-6alkyl-carbonyl (e.g., benzylcarbonyl, phenylethylcarbonyl etc.);(30) 4- to 7-membered (preferably 5- or 6-membered) monocyclic aromatic heterocyclyl-carbonyl (e.g., furylcarbonyl, thienylcarbonyl, pyrrolylcarbonyl, oxazolylcarbonyl, isoxazolylcarbonyl, thiazolylcarbonyl, isothiazolylcarbonyl, imidazolylcarbonyl, pyridylcarbonyl, pyrazolylcarbonyl etc.) containing, as a ring constituting atom besides carbon atom, 1 to 4 heteroatoms selected from a nitrogen atom, an oxygen atom and a sulfur atom;(31) 8- to 12-membered fused aromatic heterocyclyl-carbonyl (e.g., benzofurylcarbonyl, isobenzofurylcarbonyl, benzothienylcarbonyl, isobenzothienylcarbonyl, indolylcarbonyl, isoindolylcarbonyl, 1H-indazolylcarbonyl, benzimidazolylcarbonyl, benzoxazolylcarbonyl etc.) containing, as a ring constituting atom besides carbon atom, 1 to 4 heteroatoms selected from a nitrogen atom, an oxygen atom and a sulfur atom;(32) 4- to 7-membered (preferably 5- or 6-membered) non-aromatic heterocyclyl-carbonyl (e.g., oxiranylcarbonyl, azetidinylcarbonyl, oxetanylcarbonyl, thietanylcarbonyl, pyrrolidinylcarbonyl, tetrahydrofurylcarbonyl, thiolanylcarbonyl, piperidinylcarbonyl etc.) containing, as a ring constituting atom besides carbon atom, 1 to 4 heteroatoms selected from a nitrogen atom, an oxygen atom and a sulfur atom;(33) C1-6alkylsulfonyl (e.g., methylsulfonyl, ethylsulfonyl etc.);(34) C2-6alkenylsulfonyl (e.g., ethenylsulfonyl, propenylsulfonyl etc.);(35) C2-6 alkynylsulfonyl (e.g., ethynylsulfonyl, propynylsulfonyl, butynylsulfonyl, pentynylsulfonyl, hexynylsulfonyl etc.);(36) C3-8cycloalkylsulfonyl (e.g., cyclopropylsulfonyl, cyclobutylsulfonyl etc.);(37) C3-6cycloalkenylsulfonyl (e.g., cyclopropenylsulfonyl, cyclobutenylsulfonyl etc.);(38) C6-10 arylsulfonyl (e.g., phenylsulfonyl etc.);(39) C3-8 cycloalkyl-C1-6alkyl-sulfonyl (e.g., cyclopropylmethylsulfonyl etc.);(40) C3-6 cycloalkenyl-C1-6alkyl-sulfonyl (e.g., cyclopentenylmethylsulfonyl etc.);(41) C6-14 aryl-C1-6 alkyl-sulfonyl (e.g., benzylsulfonyl etc.);(42) 4- to 7-membered (preferably 5- or 6-membered) monocyclic aromatic heterocyclyl-sulfonyl (e.g., furylsulfonyl, thienylsulfonyl, pyridylsulfonyl etc.) containing, as a ring constituting atom besides carbon atom, 1 to 4 heteroatoms selected from a nitrogen atom, an oxygen atom and a sulfur atom;(43) 8- to 12-membered fused aromatic heterocyclyl-sulfonyl (e.g., benzofurylsulfonyl, isobenzofurylsulfonyl etc.) containing, as a ring constituting atom besides carbon atom, 1 to 4 heteroatoms selected from a nitrogen atom, an oxygen atom and a sulfur atom;(44) 4- to 7-membered (preferably 5- or 6-membered) non-aromatic heterocyclyl-sulfonyl (e.g., oxiranylsulfonyl, azetidinylsulfonyl etc.) containing, as a ring constituting atom besides carbon atom, 1 to 4 heteroatoms selected from a nitrogen atom, an oxygen atom and a sulfur atom;(45) amino;(46) mono-C1-6alkylamino (e.g., methylamino, ethylamino, propylamino, isopropylamino, butylamino, isobutylamino, tert-butylamino etc.);(47) di-C1-6 alkylamino (e.g., dimethylamino, diethylamino, dipropylamino, diisopropylamino, dibutylamino, diisobutylamino, di-tert-butylamino etc.);(48) mono(C1-6 alkyl-carbonyl)amino (e.g., acetylamino, ethylcarbonylamino, propylcarbonylamino, tert-butylcarbonylamino etc.) optionally having 1 to 3 halogen atoms (e.g., fluorine, chlorine, bromine, iodine);(49) mono(C6-14 arylthio (e.g., phenylthio)-C1-6 alkyl-carbonyl)amino (e.g., C1-6 alkyl-carbonylamino group such as acetylamino, ethylcarbonylamino etc.; phenylthioethylcarbonylamino etc.);(50) mono(heterocyclyl-C1-8 alkyl-carbonyl)amino (the heterocyclyl is 4- to 7-membered (preferably 5- or 6-membered) monocyclic aromatic heterocycle or monocyclic non-aromatic heterocycle (e.g., morpholinyl) containing, as a ring constituting atom besides carbon atom, 1 to 4 heteroatoms selected from an oxygen atom, a sulfur atom and a nitrogen atom) (e.g., morpholinylethylcarbonylamino etc.);(51) mono(C3-6 cycloalkyl-carbonyl)amino (e.g., cyclopropylcarbonylamino, cyclobutylcarbonylamino, cyclopentylcarbonylamino, cyclohexylcarbonylamino etc.);(52) mono(C6-14aryl-carbonyl)amino (e.g., benzoylamino etc.) optionally having 1 to 3 halogen atoms (e.g., fluorine, chlorine, bromine, iodine);(53) mono(5- to 7-membered monocyclic aromatic heterocyclyl-carbonyl)amino (which 5- to 7-membered monocyclic aromatic heterocyclyl contains, as a ring constituting atom besides carbon atom, 1 to 4 heteroatoms selected from a nitrogen atom, an oxygen atom and a sulfur atom) (e.g., furylcarbonylamino, thienylcarbonylamino, pyrrolylcarbonylamino, oxazolylcarbonylamino, isoxazolylcarbonylamino, thiazolylcarbonylamino, isothiazolylcarbonylamino, imidazolylcarbonylamino, pyridylcarbonylamino, pyrazolylcarbonylamino etc.);(54) mono(8- to 12-membered fused aromatic heterocyclyl-carbonyl)amino (which 8- to 12-membered fused aromatic heterocyclyl contains, as a ring constituting atom besides carbon atom, 1 to 4 heteroatoms selected from a nitrogen atom, an oxygen atom and a sulfur atom) (e.g., benzofurylcarbonylamino, isobenzofurylcarbonylamino, benzothienylcarbonylamino, isobenzothienylcarbonylamino etc.);(55) mono(non-aromatic heterocyclyl-carbonyl)amino (which non-aromatic heterocyclyl is 4- to 7-membered (preferably 5- or 6-membered) non-aromatic heterocycle containing, as a ring constituting atom besides carbon atom, 1 to 4 heteroatoms selected from a nitrogen atom, an oxygen atom and a sulfur atom) (e.g., oxiranylcarbonylamino, azetidinylcarbonylamino, oxetanylcarbonylamino etc.);(56) thiol;(57) C1-6 alkylsulfanyl (e.g., methylsulfanyl, ethylsulfanyl etc.);(58) C2-6 alkenylsulfanyl (e.g., ethenylsulfanyl, propenylsulfanyl etc.);(59) C2-6 alkynylsulfanyl (e.g., ethynylsulfanyl, propynylsulfanyl, butynylsulfanyl, pentynylsulfanyl, hexynylsulfanyl etc.);(60) C3-8 cycloalkylsulfanyl (e.g., cyclopropylsulfanyl, cyclobutylsulfanyl etc.);(61) C3-6 cycloalkenylsulfanyl (e.g., cyclopropenylsulfanyl, cyclobutenylsulfanyl etc.);(62) C6-14 arylsulfanyl (e.g., phenylsulfanyl etc.);(63) C3-8 cycloalkyl-C1-6 alkyl-sulfanyl (e.g., cyclopropylmethylsulfanyl etc.);(64) C3-6 cycloalkenyl-C1-6 alkyl-sulfanyl (e.g., cyclopentenylmethylsulfanyl etc.);(65) a 4- to 7-membered (preferably 5- or 6-membered) monocyclic aromatic heterocyclic group (e.g., furyl, thienyl, pyrrolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, imidazolyl, pyridyl, pyrazolyl etc.) optionally having 1 to 3 C1-4 alkyl (e.g., methyl, ethyl etc.), containing, as a ring constituting atom besides carbon atom, 1 to 4 heteroatoms selected from a nitrogen atom, an oxygen atom and a sulfur atom;(66) an 8- to 12-membered fused aromatic heterocyclic group (e.g., benzofuryl, isobenzofuryl, benzothienyl, isobenzothienyl, indolyl, isoindolyl, 1H-indazolyl, benzimidazolyl, benzoxazolyl etc.) containing, as a ring constituting atom besides carbon atom, 1 to 4 heteroatoms selected from a nitrogen atom, an oxygen atom and a sulfur atom;(67) a 4- to 7-membered (preferably 5- or 6-membered) non-aromatic heterocyclic group (e.g., oxiranyl, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, tetrahydrofuryl, thiolanyl, piperidinyl etc.) containing, as a ring constituting atom besides carbon atom, 1 to 4 heteroatoms selected from a nitrogen atom, an oxygen atom and a sulfur atom;(68) 4- to 7-membered (preferably 5- or 6-membered) monocyclic aromatic heterocyclyl-oxy (e.g., furyloxy, thienyloxy, pyrrolyloxy, oxazolyloxy, isoxazolyloxy, thiazolyloxy, isothiazolyloxy, imidazolyloxy, pyridyloxy, pyrazolyloxy etc.) containing, as a ring constituting atom besides carbon atom, 1 to 4 heteroatoms selected from a nitrogen atom, an oxygen atom and a sulfur atom;(69) 8- to 12-membered fused aromatic heterocyclyl-oxy (e.g., benzofuryloxy, isobenzofuryloxy, benzothienyloxy, isobenzothienyloxy, indolyloxy, isoindolyloxy, 1H-indazolyloxy, benzimidazolyloxy, benzoxazolyloxy etc.) containing, as a ring constituting atom besides carbon atom, 1 to 4 heteroatoms selected from a nitrogen atom, an oxygen atom and a sulfur atom;(70) 5 or 7-membered non-aromatic heterocyclyl-oxy (e.g., oxiranyloxy, azetidinyloxy, oxetanyloxy, thietanyloxy, pyrrolidinyloxy, tetrahydrofuryloxy, thiolanyloxy, piperidinyloxy etc.) containing, as a ring constituting atom besides carbon atom, 1 to 4 heteroatoms selected from a nitrogen atom, an oxygen atom and a sulfur atom;(71) oxo;(72) C1-6 alkylsulfinyl (e.g., methylsulfinyl, ethylsulfinyl etc.);(73) C2-6 alkenylsulfinyl (e.g., ethenylsulfinyl, propenylsulfinyl etc.);(74) C2-6 alkynylsulfinyl (e.g., ethynylsulfinyl, propynylsulfinyl, butynylsulfinyl, pentynylsulfinyl, hexynylsulfinyl etc.);(75) C3-8 cycloalkylsulfinyl (e.g., cyclopropylsulfinyl, cyclobutylsulfinyl etc.);(76) C3-6 cycloalkenylsulfinyl (e.g., cyclopropenylsulfinyl, cyclobutenylsulfinyl etc.);(77) C6-14 arylsulfinyl (e.g., phenylsulfinyl etc.);(78) C3-8 cycloalkyl-C1-6 alkyl-sulfinyl (e.g., cyclopropylmethylsulfinyl etc.);(79) C3-6 cycloalkenyl-C1-6alkyl-sulfinyl (e.g., cyclopentenylmethylsulfinyl etc.);(80) aminothiocarbonyl substituted by C1-6 alkyl or C6-14 aryl-C1-4 alkyl-carbonyl (e.g., methylaminothiocarbonyl, ethylaminothiocarbonyl, propylaminothiocarbonyl, benzylcarbonylaminothiocarbonyl etc.);(81) di-C1-6 alkyl-aminothiocarbonyl (e.g., dimethylaminothiocarbonyl, diethylaminothiocarbonyl, dipropylaminothiocarbonyl etc.);(82) carboxy;(83) C1-6alkoxycarbonyl (e.g., methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl, tert-butoxycarbonyl etc.);(84) C2-6 alkenyloxy-carbonyl (e.g., ethenyloxycarbonyl, propenyloxycarbonyl, butenyloxycarbonyl, pentenyloxycarbonyl, hexenyloxycarbonyl etc.);(85) C2-6 alkynyloxy-carbonyl (e.g., ethynyloxycarbonyl, propynyloxycarbonyl, butynyloxycarbonyl, pentynyloxycarbonyl, hexynyloxycarbonyl etc.);(86) C3-8 cycloalkyl-oxy-carbonyl (e.g., cyclopropyloxycarbonyl, cyclobutyloxycarbonyl, cyclopentyloxycarbonyl, cyclohexyloxycarbonyl etc.);(87) C3-6 cycloalkenyloxy-carbonyl (e.g., cyclopropenyloxycarbonyl, cyclobutenyloxycarbonyl, cyclopentenyloxycarbonyl, cyclohexenyloxycarbonyl etc.);(88) C6-14 aryloxy-carbonyl (e.g., phenyloxycarbonyl, 1-naphthyloxycarbonyl, 2-naphthyloxycarbonyl etc.);(89) C3-8 cycloalkyl-C1-6alkoxy-carbonyl (e.g., cyclopropylmethyloxycarbonyl, cyclopropylethyloxycarbonyl, cyclobutylmethyloxycarbonyl, cyclopentylmethyloxycarbonyl, cyclohexylthethyloxycarbonyl, cyclohexylethyloxycarbonyl etc.);(90) C3-6cycloalkenyl-C1-6alkoxy-carbonyl (e.g., cyclopentenylmethyloxycarbonyl, cyclohexenylmethyloxycarbonyl, cyclohexenylethyloxycarbonyl, cyclohexenylpropyloxycarbonyl etc.); and(91) C6-14 aryl-C1-6alkoxy-carbonyl (e.g., phenylmethyloxycarbonyl, phenylethyloxycarbonyl etc.) (hereinafter to be abbreviated as substituent group X). When two or more substituents are present, they may be the same or different, and preferable number of substituents is 1 to 5, more preferably 1 to 3.
Examples of the “C2-8 alkenyl group” of the above-mentioned “optionally substituted C2-8 alkenyl group” include ethenyl, 1-propenyl, 2-propenyl, 2-methyl-1-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 3-methyl-2-butenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 4-methyl-3-pentenyl, 1-hexenyl, 3-hexenyl, 5-hexenyl, 1-heptenyl, 1-octenyl and the like.
Examples of the “alkenyl group” of the above-mentioned “optionally substituted alkenyl group” may have one or more (preferably 1 to 5, more preferably 1 to 3) substituents at substitutable position(s). Examples of such substituent include substituents selected from substituent group X. When the number of the substituents is two or more, the respective substituents may be the same or different.
Examples of the “C2-8 alkynyl group” of the above-mentioned “optionally substituted C2-8 alkynyl group” include ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 3-butynyl, 1-pentynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl, 1-hexynyl, 2-hexynyl, 3-hexynyl, 4-hexynyl, 5-hexynyl, 1-heptynyl, 1-octynyl and the like.
The “alkynyl group” of the above-mentioned “optionally substituted alkynyl group” may have one or more (preferably 1 to 5, more preferably 1 to 3) substituents at substitutable position(s). Examples of such substituent include substituents selected from substituent group X. When the number of the substituents is two or more, the respective substituents may be the same or different.
Examples of the “C1-8 alkyl-carbonyl group” of the above-mentioned “optionally substituted C1-8 alkyl-carbonyl group” include acetyl, ethylcarbonyl, propylcarbonyl, isopropylcarbonyl, butylcarbonyl, isobutylcarbonyl, sec-butylcarbonyl, tert-butylcarbonyl, pentylcarbonyl, isopentylcarbonyl, neopentylcarbonyl, 1-ethylpropylcarbonyl, hexylcarbonyl, isohexylcarbonyl, 1,1-dimethylbutylcarbonyl, 2,2-dimethylbutylcarbonyl, 3,3-dimethylbutylcarbonyl, 2-ethylbutylcarbonyl, heptylcarbonyl, octylcarbonyl and the like.
The “C1-8 alkyl-carbonyl group” of the above-mentioned “optionally substituted C1-8 alkyl-carbonyl group” may have one or more (preferably 1 to 5, more preferably 1 to 3) substituents at substitutable position(s). Examples of such substituent include substituents selected from substituent group X. When the number of the substituents is two or more, the respective substituents may be the same or different.
Examples of the “C3-8 cycloalkyl group” of the above-mentioned “optionally substituted C3-8 cycloalkyl group” include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl and the like.
The “C3-8 cycloalkyl group” of the above-mentioned “optionally substituted C3-8 cycloalkyl group” may have one or more (preferably 1 to 5, more preferably 1 to 3) substituents at substitutable position(s). Examples of such substituent include substituents selected from substituent group X. When the number of the substituents is two or more, the respective substituents may be the same or different.
Examples of the “C6-18 aryl group” of the above-mentioned “optionally substituted C6-18 aryl group” include phenyl, naphthyl, anthryl, phenanthryl, acenaphthylenyl, biphenylyl and the like, and phenyl is preferable.
The “aryl group” of the above-mentioned “optionally substituted aryl group” may have one or more (preferably 1 to 5, more preferably 1 to 3) substituents at substitutable position(s). Examples of such substituent include substituents selected from substituent group X. When the number of the substituents is two or more, the respective substituents may be the same or different.
Examples of the “C6-18 aryl-C1-4 alkyl group” of the above-mentioned “optionally substituted C6-18 aryl-C1-4 alkyl group” include benzyl, phenethyl, phenylpropyl, naphthylmethyl, biphenylylmethyl and the like.
The “C6-18 aryl-C1-4 alkyl group” of the above-mentioned “optionally substituted C6-18 aryl-C1-4 alkyl group” may have one or more (preferably 1 to 5, more preferably 1 to 3) substituents at substitutable position(s). Examples of such substituent include substituents selected from substituent group X. When the number of the substituents is two or more, the respective substituents may be the same or different.
Examples of the “C6-18 aryl-carbonyl group” of the above-mentioned “optionally substituted C6-18 aryl-carbonyl group” include phenylcarbonyl, naphthylcarbonyl, anthrylcarbonyl, phenanthrylcarbonyl, acenaphthylenylcarbonyl, biphenylylcarbonyl and the like.
The “C6-18 aryl-carbonyl group” of the above-mentioned “optionally substituted C6-18 aryl-carbonyl group” may have one or more (preferably 1 to 5, more preferably 1 to 3) substituents at substitutable position(s). Examples of such substituent include substituents selected from substituent group X. When the number of the substituents is two or more, the respective substituents may be the same or different.
Examples of the “C6-18 aryl-C1-4 alkyl-carbonyl group” of the above-mentioned “optionally substituted C6-18 aryl-C1-4 alkyl-carbonyl group” include benzylcarbonyl, phenethylcarbonyl, phenylpropylcarbonyl, naphthylmethylcarbonyl, biphenylylmethylcarbonyl and the like.
The “C6-18 aryl-C1-4 alkyl-carbonyl group” of the above-mentioned “optionally substituted C6-18 aryl-C1-4 alkyl-carbonyl group” may have one or more (preferably 1 to 5, more preferably 1 to 3) substituents at substitutable position(s). Examples of such substituent include substituents selected from substituent group X. When the number of the substituents is two or more, the respective substituents may be the same or different.
Examples of the “heterocyclic group” of the above-mentioned “optionally substituted heterocyclic group” include an aromatic heterocyclic group and a non-aromatic heterocyclic group.
Examples of the aromatic heterocyclic group include a 4- to 7-membered (preferably 5- or 6-membered) monocyclic aromatic heterocyclic group containing, as a ring constituting atom besides carbon atom, 1 to 4 heteroatoms selected from an oxygen atom, a sulfur atom and a nitrogen atom, and a 8- to 12-membered fused aromatic heterocyclic group. Examples of the fused aromatic heterocyclic group include a group derived from a fused ring wherein a ring corresponding to such 4- to 7-membered monocyclic aromatic heterocyclic group, and 1 or 2 rings selected from a 5- or 6-membered aromatic heterocycle containing 1 or 2 nitrogen atoms, a 5-membered aromatic heterocycle containing one sulfur atom and a benzene ring are condensed, and the like.
Preferable examples of the aromatic heterocyclic group include a monocyclic aromatic heterocyclic group such as furyl (e.g., 2-furyl, 3-furyl), thienyl (e.g., 2-thienyl, 3-thienyl), pyridyl (e.g., 2-pyridyl, 3-pyridyl, 4-pyridyl), pyrimidinyl (e.g., 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, 6-pyrimidinyl), pyridazinyl (e.g., 3-pyridazinyl, 4-pyridazinyl), pyrazinyl (e.g., 2-pyrazinyl), pyrrolyl (e.g., 1-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl), imidazolyl (e.g., 1-imidazolyl, 2-imidazolyl, 4-imidazolyl, 5-imidazolyl), pyrazolyl (e.g., 1-pyrazolyl, 3-pyrazolyl, 4-pyrazolyl), thiazolyl (e.g., 2-thiazolyl, 4-thiazolyl, 5-thiazolyl), isothiazolyl (e.g., 3-isothiazolyl, 4-isothiazolyl, 5-isothiazolyl), oxazolyl (e.g., 2-oxazolyl, 4-oxazolyl, 5-oxazolyl), isoxazolyl (e.g., 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl), oxadiazolyl (e.g., 1,2,4-oxadiazol-5-yl, 1,3,4-oxadiazol-2-yl), thiadiazolyl (e.g., 1,3,4-thiadiazol-2-yl), triazolyl (e.g., 1,2,4-triazol-1-yl, 1,2,4-triazol-3-yl, 1,2,3-triazol-1-yl, 1,2,3-triazol-2-yl, 1,2,3-triazol-4-yl), tetrazolyl (e.g., tetrazol-1-yl, tetrazol-5-yl), triazinyl (e.g., 1,2,4-triazin-1-yl, 1,2,4-triazin-3-yl) and the like; a fused aromatic heterocyclic group such as quinolyl (e.g., 2-quinolyl, 3-quinolyl, 4-quinolyl, 6-quinolyl), isoquinolyl (e.g., 3-isoquinolyl), quinazolyl (e.g., 2-quinazolyl, 4-quinazolyl), quinoxalyl (e.g., 2-quinoxalyl, 6-quinoxalyl), benzofuryl (e.g., 2-benzofuryl3-benzofuryl), benzothienyl (e.g., 2-benzothienyl, 3-benzothienyl), benzoxazolyl (e.g., 2-benzoxazolyl), benzisoxazolyl (e.g., 7-benzisoxazolyl), benzothiazolyl (e.g., 2-benzothiazolyl), benzimidazolyl (e.g., benzimidazol-1-yl, benzimidazol-2-yl, benzimidazol-5-yl), benzotriazolyl (e.g., 1H-1,2,3-benzotriazol-5-yl), indolyl (e.g., indol-1-yl, indol-2-yl, indol-3-yl, indol-5-yl), indazolyl (e.g., 1H-indazol-3-yl), pyrrolopyrazinyl (e.g., 1H-pyrrolo[2,3-b]pyrazin-2-yl, 1H-pyrrolo[2,3-b]pyrazin-6-yl), pyrrolopyrimidinyl (e.g., 1H-pyrrolo[2,3-d]pyrimidin-2-yl, 1H-pyrrolo[2,3-d]pyrimidin-6-yl), imidazopyridinyl (e.g., 1H-imidazo[4,5-b]pyridin-2-yl, 1H-imidazo[4,5-c]pyridin-2-yl, 2H-imidazo[1,2-a]pyridin-3-yl), imidazopyrazinyl (e.g., 1H-imidazo[4,5-b]pyrazin-2-yl), pyrazolopyridinyl (e.g., 1H-pyrazolo[4,3-c]pyridin-3-yl), pyrazolothienyl (e.g., 2H-pyrazolo[3,4-b]thiophen-2-yl), pyrazolotriazinyl (e.g., pyrazolo[5,1-c][1,2,4]triazin-3-yl) and the like.
Examples of the non-aromatic heterocyclic group include a 4- to 7-membered (preferably 5- or 6-membered) monocyclic non-aromatic heterocyclic group containing, as a ring constituting atom besides carbon atom, 1 to 4 heteroatoms selected from an oxygen atom, a sulfur atom and a nitrogen atom, and a 8- to 12-membered fused non-aromatic heterocyclic group. Examples of the fused non-aromatic heterocyclic group include a group derived from a fused ring wherein a ring corresponding to such 4- to 7-membered monocyclic non-aromatic heterocyclic group, and 1 or 2 rings selected from a 5- or 6-membered heterocycle containing 1 or 2 nitrogen atoms, a 5-membered heterocycle containing one sulfur atom and a benzene ring are condensed, and the like.
Preferable examples of the non-aromatic heterocyclic group include a monocyclic non-aromatic heterocyclic group such as oxetanyl (e.g., 2-oxetanyl, 3-oxetanyl), pyrrolidinyl (e.g., 1-pyrrolidinyl, 2-pyrrolidinyl), piperidinyl (e.g., piperidino, 2-piperidinyl, 3-piperidinyl, 4-piperidinyl), morpholinyl (e.g., morpholino), thiomorpholinyl (e.g., thiomorpholino), piperazinyl (e.g., 1-piperazinyl, 2-piperazinyl, 3-piperazinyl), hexamethyleniminyl (e.g., hexamethylenimin-1-yl), oxazolidinyl (e.g., oxazolidin-2-yl), thiazolidinyl (e.g., thiazolidin-2-yl), imidazolidinyl (e.g., imidazolidin-2-yl, imidazolidin-3-yl), oxazolinyl (e.g., oxazolin-2-yl), thiazolinyl (e.g., thiazolin-2-yl), imidazolinyl (e.g., imidazolin-2-yl, imidazolin-3-yl), dioxolyl (e.g., 1,3-dioxol-4-yl), dioxolanyl (e.g., 1,3-dioxolan-4-yl), dihydrooxadiazolyl (e.g., 4,5-dihydro-1,2,4-oxadiazol-3-yl), 2-thioxo-1,3-oxazolidin-5-yl, pyranyl (e.g., 4-pyranyl), tetrahydropyranyl (e.g., 2-tetrahydropyranyl, 3-tetrahydropyranyl, 4-tetrahydropyranyl), thiopyranyl (e.g., 4-thiopyranyl), tetrahydrothiopyranyl (e.g., 2-tetrahydrothiopyranyl, 3-tetrahydrothiopyranyl, 4-tetrahydrothiopyranyl), 1-oxidotetrahydrothiopyranyl (e.g., 1-oxidotetrahydrothiopyran-4-yl), 1,1-dioxidotetrahydrothiopyranyl (e.g., 1,1-dioxidotetrahydrothiopyran-4-yl), tetrahydrofuryl (e.g., tetrahydrofuran-3-yl, tetrahydrofuran-2-yl), pyrazolidinyl (e.g., pyrazolidin-1-yl, pyrazolidin-3-yl), pyrazolinyl (e.g., pyrazolin-1-yl), tetrahydropyrimidinyl (e.g., tetrahydropyrimidin-1-yl), dihydrotriazolyl (e.g., 2,3-dihydro-1H-1,2,3-triazol-1-yl), tetrahydrotriazolyl (e.g., 2,3,4,5-tetrahydro-1H-1,2,3-triazol-1-yl) and the like; a fused non-aromatic heterocyclic group such as dihydroindolyl (e.g., 2,3-dihydro-1H-indol-1-yl), dihydroisoindolyl (e.g., 1,3-dihydro-2H-isoindol-2-yl), dihydrobenzofuranyl (e.g., 2,3-dihydro-1-benzofuran-5-yl), dihydrobenzodioxinyl (e.g., 2,3-dihydro-1,4-benzodioxinyl), dihydrobenzodioxepinyl (e.g., 3,4-dihydro-2H-1,5-benzodioxepinyl), tetrahydrobenzofuranyl (e.g., 4,5,6,7-tetrahydro-1-benzofuran-3-yl), chromenyl (e.g., 4H-chromen-2-yl, 2H-chromen-3-yl), dihydroquinolinyl (e.g., 1,2-dihydroquinolin-4-yl), tetrahydroquinolinyl (e.g., 1,2,3,4-tetrahydroquinolin-4-yl), dihydroisoquinolinyl (e.g., 1,2-dihydroisoquinolin-4-yl), tetrahydroisoquinolinyl (e.g., 1,2,3,4-tetrahydroisoquinolin-4-yl), dihydrophthalazinyl (e.g., 1,4-dihydrophthalazin-4-yl) and the like.
The “heterocyclic group” of the above-mentioned “optionally substituted heterocyclic group” may have one or more (preferably 1 to 5, more preferably 1 to 3) substituents at substitutable position(s). Examples of such substituent include substituents selected from substituent group X. When the number of the substituents is two or more, the respective substituents may be the same or different.
Examples of the above-mentioned “optionally substituted heterocyclyl-C1-4 alkyl group” include a group wherein C1-4 alkyl (e.g., methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl) is substituted by the above-mentioned “optionally substituted heterocyclic group”.
Examples of the above-mentioned “optionally substituted heterocyclyl-carbonyl group” include a group wherein carbonyl is bonded to the above-mentioned “optionally substituted heterocyclic group”.
Examples of the above-mentioned “optionally substituted heterocyclyl-C1-4 alkyl-carbonyl group” include a group wherein carbonyl is bonded to the above-mentioned “optionally substituted heterocyclyl-C1-4 alkyl group”.
The “carbamoyl group” of the above-mentioned “optionally substituted carbamoyl group” may have 1 or 2 substituents. Examples of such substituent include the aforementioned optionally substituted C1-8 alkyl group, optionally substituted C2-8 alkenyl group, optionally substituted C2-8 alkynyl group, optionally substituted C1-8 alkyl-carbonyl group, optionally substituted C3-8 cycloalkyl group, optionally substituted C6-18 aryl group, optionally substituted C6-18 aryl-C1-4 alkyl group, optionally substituted C6-18 aryl-carbonyl group, optionally substituted C6-18 aryl-C1-4 alkyl-carbonyl group, optionally substituted heterocyclic group (heterocyclic group bonded via a carbon atom), optionally substituted heterocyclyl-C1-4 alkyl group, optionally substituted heterocyclyl-carbonyl group and optionally substituted heterocyclyl-C1-4 alkyl-carbonyl group. When the number of the substituents is two or more, the respective substituents may be the same or different.
Examples of the “optionally substituted group bonded via a nitrogen atom” include
(i) amino,
(ii) amino monosubstituted by the above-mentioned “optionally substituted group bonded via a carbon atom”,
(iii) amino disubstituted by the above-mentioned “optionally substituted group bonded via a carbon atom”, preferably C1-6 alkyl (e.g., methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl etc.), and
(iv) the above-mentioned optionally substituted heterocyclic group (heterocyclic group bonded via a nitrogen atom) and the like.
Examples of the “optionally substituted group bonded via an oxygen atom” include hydroxy optionally substituted by the above-mentioned “optionally substituted group bonded via a carbon atom”.
Examples of the “optionally substituted group bonded via a sulfur atom” include mercapto optionally substituted by the above-mentioned “optionally substituted group bonded via a carbon atom”. The sulfur atom may be oxidized.
HY is an optionally substituted nitrogen-containing aromatic heterocyclic group (excluding 3-isoxazolyl group, 2-pyridyl group, 3-pyridyl group, 5-pyrimidyl group, 2-pyrimidyl group and pyrazinyl group).
Examples of the “nitrogen-containing aromatic heterocyclic group” include a 4- to 7-membered (preferably 5- or 6-membered) monocyclic nitrogen-containing aromatic heterocyclic group containing, as a ring constituting atom, carbon atom and 1 to 4 nitrogen atoms, and further, optionally containing 1 or 2 heteroatoms selected from an oxygen atom and a sulfur atom, and a 8- to 12-membered fused nitrogen-containing aromatic heterocyclic group. Examples of the fused nitrogen-containing aromatic heterocyclic group include a group derived from a fused ring wherein a ring corresponding to such 4- to 7-membered monocyclic nitrogen-containing aromatic heterocyclic group, and 1 or 2 rings selected from a 5- or 6-membered aromatic heterocycle containing 1 or 2 nitrogen atoms, a 5-membered aromatic heterocycle containing one sulfur atom and a benzene ring are fused, and the like.
Preferable examples of the nitrogen-containing aromatic heterocyclic group include a monocyclic nitrogen-containing aromatic heterocyclic group such as pyridyl (e.g., 2-pyridyl, 3-pyridyl, 4-pyridyl), pyrimidinyl (e.g., 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, 6-pyrimidinyl), pyridazinyl (e.g., 3-pyridazinyl, 4-pyridazinyl), pyrazinyl (e.g., 2-pyrazinyl), pyrrolyl (e.g., 1-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl), imidazolyl (e.g., 1-imidazolyl, 2-imidazolyl, 4-imidazolyl, 5-imidazolyl), pyrazolyl (e.g., 1-pyrazolyl, 3-pyrazolyl, 4-pyrazolyl), thiazolyl (e.g., 2-thiazolyl, 4-thiazolyl, 5-thiazolyl), isothiazolyl (e.g., 3-isothiazolyl, 4-isothiazolyl, 5-isothiazolyl), oxazolyl (e.g., 2-oxazolyl, 4-oxazolyl, 5-oxazolyl), isoxazolyl (e.g., 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl), oxadiazolyl (e.g., 1,2,4-oxadiazol-5-yl, 1,3,4-oxadiazol-2-yl), thiadiazolyl (e.g., 1,3,4-thiadiazol-2-yl), triazolyl (e.g., 1,2,4-triazol-1-yl, 1,2,4-triazol-3-yl, 1,2,3-triazol-1-yl, 1,2,3-triazol-2-yl, 1,2,3-triazol-4-yl), tetrazolyl (e.g., tetrazol-1-yl, tetrazol-5-yl), triazinyl (e.g., 1,2,4-triazin-1-yl, 1,2,4-triazin-3-yl) and the like; a fused nitrogen-containing aromatic heterocyclic group such as quinolyl (e.g., 2-quinolyl, 3-quinolyl, 4-quinolyl, 6-quinolyl), isoquinolyl (e.g., 3-isoquinolyl), quinazolyl (e.g., 2-quinazolyl, 4-quinazolyl), quinoxalyl (e.g., 2-quinoxalyl, 6-quinoxalyl), benzoxazolyl (e.g., 2-benzoxazolyl), benzisoxazolyl (e.g., 7-benzisoxazolyl), benzothiazolyl (e.g., 2-benzothiazolyl), benzimidazolyl (e.g., benzimidazol-1-yl, benzimidazol-2-yl, benzimidazol-5-yl), benzotriazolyl (e.g., 1H-1,2,3-benzotriazol-5-yl), indolyl (e.g., indol-1-yl, indol-2-yl, indol-3-yl, indol-5-yl), indazolyl (e.g., 1H-indazol-3-yl), pyrrolopyrazinyl (e.g., 1H-pyrrolo[2,3-b]pyrazin-2-yl, 1H-pyrrolo[2,3-b]pyrazin-6-yl), pyrrolopyrimidinyl (e.g., 1H-pyrrolo[2,3-d]pyrimidin-2-yl, 1H-pyrrolo[2,3-d]pyrimidin-6-yl), imidazopyridinyl (e.g., 1H-imidazo[4,5-b]pyridin-2-yl, 1H-imidazo[4,5-c]pyridin-2-yl, 2H-imidazo[1,2-a]pyridin-3-yl), imidazopyrazinyl (e.g., 1H-imidazo[4,5-b]pyrazin-2-yl), pyrazolopyridinyl (e.g., 1H-pyrazolo[4,3-c]pyridin-3-yl), tetrahydropyrazolopyridyl, pyrazolothienyl (e.g., 2H-pyrazolo[3,4-b]thiophen-2-yl), pyrazolotriazinyl (e.g., pyrazolo[5,1-c][1,2,4]triazin-3-yl) and the like.
As preferable examples of the substituent of the “nitrogen-containing aromatic heterocyclic group”, a group selected from a substituent group consisting of
(1) a halogen atom (e.g., fluorine, chlorine, bromine, iodine);
(2) cyano;
(3) nitro;
(4) an optionally substituted hydrocarbon group;
(5) an optionally substituted heterocyclic group;
(6) a formyl group;
(7) an optionally substituted hydrocarbon-carbonyl group;
(8) an optionally substituted heterocyclyl-carbonyl group;
(9) an optionally substituted hydroxy group, specifically a hydroxy group optionally substituted by a group selected from an optionally substituted hydrocarbon group and an optionally substituted heterocyclic group;
(10) an optionally substituted amino group, specifically an amino group optionally substituted by 1 or 2 groups selected from an optionally substituted hydrocarbon group, an optionally substituted heterocyclic group, an optionally substituted hydrocarbon-carbonyl group and an optionally substituted heterocyclyl-carbonyl group;(11) an optionally substituted carbamoyl group, specifically a carbamoyl group optionally substituted by 1 or 2 groups selected from an optionally substituted hydrocarbon group, an optionally substituted heterocyclic group, an optionally substituted hydrocarbon-carbonyl group and an optionally substituted heterocyclyl-carbonyl group;(12) an optionally substituted sulfonyl group, specifically a sulfonyl group optionally substituted by a group selected from an optionally substituted hydrocarbon group and an optionally substituted heterocyclic group;(13) an optionally substituted sulfamoyl group, specifically a sulfamoyl group optionally substituted by a group selected from an optionally substituted hydrocarbon group and an optionally substituted heterocyclic group; and(14) an optionally esterified carboxyl group, specifically a carboxyl group optionally esterified by a group selected from an optionally substituted hydrocarbon group and an optionally substituted heterocyclic group, preferably an optionally substituted alkoxycarbonyl group, particularly preferably a carboxyl group optionally esterified by C1-8alkyl (e.g., C1-6 alkyl such as methyl, ethyl and the like) (hereinafter to be abbreviated as substituent group Y) can be used. Particularly, a group selected from the above-mentioned substituent group X can be used.
As the “optionally substituted hydrocarbon group” in the explanation of substituent group Y, an optionally substituted alkyl group (preferably C1-20 alkyl group, particularly preferably C1-8 alkyl group), an optionally substituted alkenyl group (preferably C2-8 alkenyl group), an optionally substituted alkynyl group (preferably C2-8 alkynyl group), an optionally substituted C3-8 cycloalkyl group, an optionally substituted aryl group (preferably C6-18 aryl group), an optionally substituted C6-18 aryl-C1-4 alkyl group and the like, which are exemplified as “optionally substituted group bonded via a carbon atom”, can be used.
As the “optionally substituted heterocyclic group” in the explanation of substituent group Y, a group similar to the optionally substituted heterocyclic group exemplified as the “optionally substituted group bonded via a carbon atom” can be used.
As the “optionally substituted hydrocarbon” of the “optionally substituted hydrocarbon-carbonyl group” in the explanation of substituent group Y, a group similar to the above-mentioned “optionally substituted hydrocarbon group” can be used.
As the “optionally substituted heterocyclyl” of the “optionally substituted heterocyclyl-carbonyl group” in the explanation of substituent group Y, a group similar to the optionally substituted heterocyclic group exemplified as the “optionally substituted group bonded via a carbon atom” can be used.
As the “optionally substituted carbamoyl group” in the explanation of substituent group Y, a group similar to the optionally substituted carbamoyl group exemplified as the “optionally substituted group bonded via a carbon atom” can be used.
Among these, as the substituent of the “nitrogen-containing aromatic heterocyclic group”, a halogen atom, an optionally substituted hydrocarbon group, an optionally substituted heterocyclic group, an optionally substituted hydroxy group, an optionally substituted amino group and the like are preferable. As the substituent of the monocyclic nitrogen-containing aromatic heterocyclic group (e.g., 4-pyridyl, pyrimidyl, pyrazolyl, particularly 4-pyridyl), particularly preferred are an optionally substituted amino group, particularly (1) C1-8 alkyl-carbonylamino (e.g., C1-6 alkyl-carbonylamino such as acetylamino, phenoxyacetylamino, ethylcarbonylamino, propylcarbonylamino, isopropylcarbonylamino, tert-butylcarbonylamino and the like; phenylthioethylcarbonylamino; thienylmethylcarbonyl, morpholinylethylcarbonylamino and the like) optionally substituted by substituent(s) selected from C6-18 arylthio (e.g., phenylthio), C6-18 aryloxy (e.g., phenoxy), a 4- to 7-membered (preferably 5- or 6-membered) monocyclic aromatic heterocyclic group (e.g., thienyl) containing, as a ring constituting atom besides carbon atom, 1 to 4 heteroatoms selected from an oxygen atom, a sulfur atom and a nitrogen atom and a monocyclic non-aromatic heterocyclic group (e.g., morpholinyl) containing, as a ring constituting atom besides carbon atom, 1 to 4 heteroatoms selected from an oxygen atom, a sulfur atom and a nitrogen atom, (2) C3-8 cycloalkyl-carbonylamino (e.g., cyclopropylcarbonylamino, cyclopentyl, cyclohexylcarbonylamino), (3) C6-18 aryl-carbonylamino (e.g., fluorophenylcarbonyl, chlorophenylcarbonyl, difluorophenylcarbonyl, methoxyphenylcarbonyl, dimethylaminophenylcarbonylamino) optionally substituted by a substituent(s) selected from a halogen atom, C1-6 alkoxy, amino and mono- or di-C1-6 alkylamino, (4) C6-18 aryl-C1-4 alkyl-carbonylamino (e.g., benzylcarbonylamino), (5) 4- to 7-membered (preferably 5- or 6-membered) monocyclic heterocyclyl (e.g., furyl, thienyl, isoxazolyl, pyridyl)-carbonylamino (e.g., furylcarbonylamino, methylisoxazolyl), said monocyclic heterocyclyl contains, as a ring constituting atom besides carbon atom, 1 to 4 heteroatoms selected from an oxygen atom, a sulfur atom and a nitrogen atom and is optionally substituted by C1-6 alkyl.
More specifically, preferable examples of HY include
(i) a group represented by
wherein A is a cyclic group and X is CH or N, optionally substituted by the above-mentioned substituent(s), particularly, (1) hydroxy, (2) C1-6 alkyl such as methyl, ethyl and the like, (3) C1-6 alkoxy optionally substituted by hydroxy, (4) C6-18 aryl-C1-4 alkyl-oxy (e.g., benzyloxy), (5) 4- to 7-membered (preferably 5- or 6-membered) monocyclic aromatic heterocyclyl-C1-4 alkyl-oxy containing, as a ring constituting atom besides carbon atom, 1 to 4 heteroatoms selected from an oxygen atom, a sulfur atom and a nitrogen atom, (6) 4- to 7-membered (preferably 5- or 6-membered) monocyclic non-aromatic heterocyclyl-C1-4 alkyl-oxy (e.g., morpholinylethyloxy, piperidinylethyloxy) containing, as a ring constituting atom besides carbon atom, 1 to 4 heteroatoms selected from an oxygen atom, a sulfur atom and a nitrogen atom, and the like, or(ii) a 4-pyridyl group, a pyrimidinyl group, a pyrazolyl group, a thiazolyl group, an oxazolyl group, an imidazolyl group, a triazolyl group, an isothiazolyl group or a pyridazinyl group, particularly a 4-pyridyl group and the like, which are optionally substituted by the above-mentioned substituent(s), particularly, (1) a halogen atom (e.g., chlorine atom), (2) C1-6 alkyl (e.g., methyl, ethyl, propyl), (3) C1-8 alkyl-carbonylamino (e.g., C1-6alkyl-carbonylamino such as acetylamino, phenoxyacetylamino, ethylcarbonylamino, propylcarbonylamino, isopropylcarbonylamino, tert-butylcarbonylamino and the like; phenylthioethylcarbonylamino; thienylmethylcarbonyl, morpholinylethylcarbonylamino and the like) optionally substituted by substituent(s) selected from C6-18 arylthio (e.g., phenylthio), C6-18 aryloxy (e.g., phenoxy), and 4- to 7-membered (preferably 5- or 6-membered) monocyclic aromatic heterocyclic group (e.g., thienyl) or monocyclic non-aromatic heterocyclic group (e.g., morpholinyl) containing, as a ring constituting atom besides carbon atom, 1 to 4 heteroatoms selected from an oxygen atom, a sulfur atom and a nitrogen atom, (4) cycloalkyl-carbonylamino (e.g., cyclopropylcarbonylamino, cyclopentylcarbonylamino, cyclohexylcarbonylamino), (5) C6-18 aryl-carbonylamino (e.g., fluorophenylcarbonylamino, chlorophenylcarbonylamino, difluorophenylcarbonylamino, methylphenylcarbonylamino, methoxyphenylcarbonylamino, dimethylaminophenylcarbonylamino) optionally substituted by a substituent(s) selected from a halogen atom, C1-6 alkyl, C1-6 alkoxy, amino and mono- or di-C1-6 alkylamino, (6) C6-18 aryl-C1-4 alkyl-carbonylamino (e.g., benzylcarbonylamino) and (7) 4- to 7-membered (preferably 5- or 6-membered) monocyclic heterocyclyl (e.g., furyl, thienyl, isoxazolyl, pyridyl)-carbonylamino (e.g., furylcarbonylamino, methylisoxazolylcarbonylamino), said monocyclic heterocyclyl contains, as a ring constituting atom besides carbon atom, 1 to 4 heteroatoms selected from an oxygen atom, a sulfur atom and a nitrogen atom and is optionally substituted by C1-6 alkyl.
As the cyclic group for A, cyclic hydrocarbon or heterocycle can be used.
As the cyclic hydrocarbon, C6-18 cyclic hydrocarbon such as benzene, naphthalene and the like, C3-8 cycloalkane such as cyclopentane, cyclohexane, cycloheptane, cyclooctane, etc. and the like are used.
As the heterocycle, a ring corresponding to the heterocyclic group exemplified as the group bonded via a carbon atom can be used.
As HY, a 4-pyridyl group, a 4-pyrimidyl group, a pyrazolyl group or a thiazolyl group, particularly a 4-pyridyl group, optionally substituted by substituent(s) selected from (1) C1-8 alkyl-carbonylamino (e.g., C1-6 alkyl-carbonylamino such as acetylamino, phenoxyacetylamino, ethylcarbonylamino, propylcarbonylamino, isopropylcarbonylamino, tert-butylcarbonylamino and the like; phenylthioethylcarbonylamino; thienylmethylcarbonyl, morpholinylethylcarbonylamino and the like) optionally substituted by substituent(s) selected from C6-18 arylthio (e.g., phenylthio), C6-18 aryloxy (e.g., phenoxy), and 4- to 7-membered (preferably 5- or 6-membered) monocyclic aromatic heterocyclic group (e.g., thienyl) or monocyclic non-aromatic heterocyclic group (e.g., morpholinyl) containing, as a ring constituting atom besides carbon atom, 1 to 4 heteroatoms selected from an oxygen atom, a sulfur atom and a nitrogen atom, (2) C3-8 cycloalkyl-carbonylamino (e.g., cyclopropylcarbonylamino, cyclopentylcarbonylamino, cyclohexylcarbonylamino), (3) C6-18 aryl-carbonylamino (e.g., fluorophenylcarbonylamino, chlorophenylcarbonylamino, difluorophenylcarbonylamino, methylphenylcarbonylamino, methoxyphenylcarbonylamino, dimethylaminophenylcarbonylamino) optionally substituted by substituent(s) selected from a halogen atom, C1-6 alkyl, C1-6 alkoxy, amino and mono- or di-C1-6 alkylamino, (4) C6-18 aryl-C1-4 alkyl-carbonylamino (e.g., benzylcarbonylamino) and (5) 4- to 7-membered (preferably 5- or 6-membered) monocyclic heterocyclyl (e.g., furyl, thienyl, isoxazolyl, pyridyl)-carbonylamino (e.g., furylcarbonylamino, methyl isoxazolylcarbonylamino), said monocyclic heterocyclyl contains, as a ring constituting atom besides carbon atom, 1 to 4 heteroatoms selected from an oxygen atom, a sulfur atom and a nitrogen atom and is optionally substituted by C1-6 alkyl, is preferable.
Particularly, as HY,
(i) a group represented by
particularly, a group represented by
optionally substituted by the above-mentioned substituent(s), particularly, (1) hydroxy, (2) C1-6 alkyl such as methyl and the like which is optionally substituted by 4- to 7-membered (preferably 5- or 6-membered) monocyclic aromatic heterocyclyl-carbonyl-amino or C1-6 alkylcarbonylamino optionally substituted by amino containing, as a ring constituting atom besides carbon atom, 1 to 4 heteroatoms selected from an oxygen atom, a sulfur atom and a nitrogen atom, (3) C1-6 alkoxy optionally substituted by hydroxy, (4) C6-18 aryl-C1-4 alkyl-oxy (e.g., benzyloxy), (5) 4- to 7-membered (preferably 5- or 6-membered) monocyclic aromatic heterocyclyl-C1-4 alkyl-oxy containing, as a ring constituting atom besides carbon atom, 1 to 4 heteroatoms selected from an oxygen atom, a sulfur atom and a nitrogen atom which is optionally substituted by C1-6 alkyl optionally substituted by halogen, (6) 4- to 7-membered (preferably 5- or 6-membered) monocyclic non-aromatic heterocyclyl-C1-4alkyl-oxy (e.g., morpholinylethyloxy, piperidinylethyloxy) containing, as a ring constituting atom besides carbon atom, 1 to 4 heteroatoms selected from an oxygen atom, a sulfur atom and a nitrogen atom and the like (e.g., hydroxy, C1-6 alkyl such as methyl and the like) as well as (7) halogen, (8) C2-6 alkenyl, (9)C3-8 cycloalkyl, (10) C6-18 aryl optionally substituted by C1-6 alkoxy or halogen, (11) 4- to 7-membered (preferably 5- or 6-membered) monocyclic aromatic heterocyclyl containing, as a ring constituting atom besides carbon atom, 1 to 4 heteroatoms selected from an oxygen atom, a sulfur atom and a nitrogen atom which is optionally substituted by C1-6 alkyl, (12) 4- to 7-membered (preferably 5- or 6-membered) monocyclic non-aromatic heterocyclyl containing, as a ring constituting atom besides carbon atom, 1 to 4 heteroatoms selected from an oxygen atom, a sulfur atom and a nitrogen atom which is optionally substituted by C1-6 alkyl,(ii) a group represented by
optionally substituted by the above-mentioned substituent(s), particularly, (1) hydroxy, (2) C1-6 alkyl such as methyl and the like which is optionally substituted by 4- to 7-membered (preferably 5- or 6-membered) monocyclic aromatic heterocyclyl-carbonyl-amino or C1-6 alkylcarbonylamino optionally substituted by amino containing, as a ring constituting atom besides carbon atom, 1 to 4 heteroatoms selected from an oxygen atom, a sulfur atom and a nitrogen atom, (3) C1-6 alkoxy optionally substituted by hydroxy, (4) C6-18 aryl-C1-4alkyl-oxy (e.g., benzyloxy), (5) 4- to 7-membered (preferably 5- or 6-membered) monocyclic aromatic heterocyclyl-C1-4 alkyl-oxy containing, as a ring constituting atom besides carbon atom, 1 to 4 heteroatoms selected from an oxygen atom, a sulfur atom and a nitrogen atom, which is optionally substituted by C1-6 alkyl optionally substituted by halogen (6) 4- to 7-membered (preferably 5- or 6-membered) monocyclic non-aromatic heterocyclyl-C1-4alkyl-oxy (e.g., morpholinylethyloxy, piperidinylethyloxy) containing, as a ring constituting atom besides carbon atom, 1 to 4 heteroatoms selected from an oxygen atom, a sulfur atom and a nitrogen atom and the like (e.g., hydroxy, C1-6 alkyl such as methyl and the like) as well as (7) halogen, (8) C2-6 alkenyl, (9)C3-8 cycloalkyl, (10) C6-18 aryl optionally substituted by C1-6 alkoxy or halogen, (11) 4- to 7-membered (preferably 5- or 6-membered) monocyclic aromatic heterocyclyl containing, as a ring constituting atom besides carbon atom, 1 to 4 heteroatoms selected from an oxygen atom, a sulfur atom and a nitrogen atom which is optionally substituted by C1-6 alkyl, (12) 4- to 7-membered (preferably 5- or 6-membered) monocyclic non-aromatic heterocyclyl containing, as a ring constituting atom besides carbon atom, 1 to 4 heteroatoms selected from an oxygen atom, a sulfur atom and a nitrogen atom which is optionally substituted by C1-6 alkyl, or(iii) a group represented by
wherein Ra and Rc are each a hydrogen atom, an alkyl group (for example, the aforementioned C1-20 alkyl group, preferably the aforementioned C1-6 alkyl group) or a halogen atom,Rb is (i) a hydrogen atom, (ii) an optionally substituted hydrocarbon-carbonyl group, (iii) an optionally substituted heterocyclyl-carbonyl group, (iv) an optionally substituted carbamoyl group, (v) an optionally substituted alkoxycarbonyl group, (vi) an optionally substituted hydrocarbon-sulfonyl group, (vii) an optionally substituted heterocyclyl-sulfonyl group, (viii) an optionally substituted sulfamoyl group, (ix) an optionally substituted hydrocarbon group or (x) an optionally substituted heterocyclic group, andRd is (i) a hydrogen atom, (ii) an optionally substituted hydrocarbon group or (iii) an optionally substituted heterocyclic group, particularly a group represented by
and the like, is preferable.
As the alkyl group for Ra or Rc, a C1-20 alkyl group, preferably a C1-8 alkyl group such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, 1-ethylpropyl, hexyl, isohexyl, 1,1-dimethylbutyl, 2,2-dimethylbutyl, 3,3-dimethylbutyl, 2-ethylbutyl, heptyl, octyl and the like can be used. Of these, a C1-6 alkyl group such as methyl, ethyl, propyl and the like are preferable.
As the halogen atom for Ra or Rc, a fluorine atom, a chlorine atom, a bromine atom and an iodine atom can be used. Of these, a chlorine atom is preferable.
As the “optionally substituted hydrocarbon-carbonyl group” for Rb, a group similar to the “optionally substituted hydrocarbon-carbonyl group” of the aforementioned substituent group Y can be used.
As the “optionally substituted heterocyclyl-carbonyl group” for Rb, a group similar to the “optionally substituted heterocyclyl-carbonyl group” of the aforementioned substituent group Y can be used.
As the “optionally substituted carbamoyl group” for Rb, those similar to the “optionally substituted carbamoyl group” exemplified as the “optionally substituted group bonded via a carbon atom” can be used.
As the “optionally substituted alkoxycarbonyl group” for Rb, a C1-8 alkoxycarbonyl group (e.g., methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl and the like) optionally substituted by substituent(s) selected from the aforementioned substituent group X and the like can be used.
As the “optionally substituted hydrocarbon” of the “optionally substituted hydrocarbon-sulfonyl group” for Rb, a group similar to the “optionally substituted hydrocarbon group” of the aforementioned substituent group Y can be used.
As the “optionally substituted heterocyclyl” of the “optionally substituted heterocyclyl-sulfonyl group” for Rb, a group similar to the “optionally substituted heterocyclic group” of the aforementioned substituent group Y can be used.
As the “optionally substituted sulfamoyl group” for Rb, a group similar to the “optionally substituted sulfamoyl group” of the aforementioned substituent group Y can be used.
As the “optionally substituted hydrocarbon group” for Rb, a group similar to the “optionally substituted hydrocarbon group” of the aforementioned substituent group Y can be used.
As the “optionally substituted heterocyclic group” for Rb, a group similar to the “optionally substituted heterocyclic group” of the aforementioned substituent group Y can be used.
As the “optionally substituted hydrocarbon group” for Rd, a group similar to the “optionally substituted hydrocarbon group” of the aforementioned substituent group Y can be used.
As the “optionally substituted heterocyclic group” for Rd, a group similar to the “optionally substituted heterocyclic group” of the aforementioned substituent group Y can be used.
As Ra, a hydrogen atom, a halogen atom (e.g., chlorine atom), a C1-6 alkyl group such as methyl, ethyl, propyl and the like are preferable.
As Rb, (1) a hydrogen atom, (2) a C1-8 alkyl-carbonyl group (e.g., C1-6 alkyl-carbonyl group such as acetyl, ethylcarbonyl and the like) optionally substituted by a substituent(s) selected from C6-18 arylthio (e.g., phenylthio), 4- to 7-membered (preferably 5- or 6-membered) monocyclic aromatic heterocyclic group or monocyclic non-aromatic heterocyclic group (e.g., morpholinyl) containing, as a ring constituting atom besides carbon atom, 1 to 4 heteroatoms selected from an oxygen atom, a sulfur atom and a nitrogen atom, and the like, (3) a C3-8 cycloalkyl-carbonyl group (e.g., cyclopropylcarbonyl) and the like are preferable.
As Rc or Rd, a hydrogen atom, a C1-6 alkyl group such as methyl, ethyl, propyl and the like, and the like are preferable.
In addition, preferable examples of HY include
(i) a 8- to 10-membered nitrogen-containing aromatic fused heterocyclic group containing, besides carbon atom and nitrogen atom, 1 to 4 heteroatoms selected from an oxygen atom and a sulfur atom, which is optionally substituted by substituent(s) selected from (1) hydroxy, (2) C1-6 alkyl such as methyl and the like, (3) C1-6 alkoxy optionally substituted by hydroxy, (4) C6-18 aryl-C1-4 alkyl-oxy (e.g., benzyloxy), (5) 4- to 7-membered (preferably 5- or 6-membered) monocyclic aromatic heterocyclyl-C1-4 alkyl-oxy containing, as a ring constituting atom besides carbon atom, 1 to 4 heteroatoms selected from an oxygen atom, a sulfur atom and a nitrogen atom and (6) 4- to 7-membered (preferably 5- or 6-membered) monocyclic non-aromatic heterocyclyl-C1-4 alkyl-oxy (e.g., morpholinylethyloxy, piperidinylethyloxy) containing, as a ring constituting atom besides carbon atom, 1 to 4 heteroatoms selected from an oxygen atom, a sulfur atom and a nitrogen atom,(ii) a 4-pyridyl group or a pyrazolyl group, particularly a 4-pyridyl group, optionally substituted by substituent(s) selected from (1) a halogen atom (e.g., a chlorine atom), (2) C1-6 alkyl (e.g., methyl, ethyl, propyl), (3) C1-8 alkyl-carbonylamino (e.g., C1-6 alkyl-carbonylamino such as acetylamino, phenoxyacetylamino, ethylcarbonylamino, propylcarbonylamino, isopropylcarbonylamino, tert-butylcarbonylamino and the like; phenylthioethylcarbonylamino; thienylmethylcarbonyl, morpholinylethylcarbonylamino and the like) optionally substituted by substituent(s) selected from C6-18 arylthio (e.g., phenylthio), C6-18 aryloxy (e.g., phenoxy), and 4- to 7-membered (preferably 5- or 6-membered) monocyclic aromatic heterocyclic group (e.g., thienyl) or monocyclic non-aromatic heterocyclic group (e.g., morpholinyl) containing, as a ring constituting atom besides carbon atom, 1 to 4 heteroatoms selected from an oxygen atom, a sulfur atom and a nitrogen atom, (4) C3-8 cycloalkyl-carbonylamino (e.g., cyclopropylcarbonylamino, cyclopentylcarbonylamino, cyclohexylcarbonylamino), (5) C6-18 aryl-carbonylamino (e.g., fluorophenylcarbonylamino, chlorophenylcarbonylamino, difluorophenylcarbonylamino, methylphenylcarbonylamino, methoxyphenylcarbonylamino, dimethylaminophenylcarbonylamino) optionally substituted by substituent(s) selected from a halogen atom, C1-6 alkyl, C1-6 alkoxy, amino and mono- or di-C1-6 alkylamino, (6) C6-18 aryl-C1-4 alkyl-carbonylamino (e.g., benzylcarbonylamino) and (7) 4- to 7-membered (preferably 5- or 6-membered) monocyclic heterocyclyl (e.g., furyl, thienyl, isoxazolyl, pyridyl)-carbonylamino (e.g., furylcarbonylamino, methylisoxazolylcarbonylamino), said monocyclic heterocyclyl contains, as a ring constituting atom besides carbon atom, 1 to 4 heteroatoms selected from an oxygen atom, a sulfur atom and a nitrogen atom and is optionally substituted by C1-6 alkyl, and the like.
R2 is a halogen atom, or the aforementioned optionally substituted group bonded via a carbon atom, a nitrogen atom, an oxygen atom or a sulfur atom. Particularly, (i) a halogen atom, (ii) an optionally substituted hydroxy group, (iii) an optionally substituted hydrocarbon group, (iv) an optionally substituted heterocyclic group, (v) an optionally substituted amino group, (vi) an optionally substituted thiol group or (vii) an acyl group is preferable.
As the halogen atom, a fluorine atom, a chlorine atom, a bromine atom or an iodine atom is used.
As the “optionally substituted hydroxy group”, a group similar to the “optionally substituted hydroxy group” for the aforementioned substituent group Y is used.
As the “optionally substituted hydrocarbon group”, a group similar to the “optionally substituted hydrocarbon group” for the aforementioned substituent group Y is used.
As the “optionally substituted heterocyclic group”, a group similar to the “optionally substituted heterocyclic group” for the aforementioned substituent group Y is used.
As the “optionally substituted amino group”, a group similar to the “optionally substituted amino group” for the aforementioned substituent group Y is used.
As the “optionally substituted thiol group”, a thiol group optionally substituted by the “optionally substituted hydrocarbon group” for the aforementioned substituent group Y or the “optionally substituted heterocyclic group” for the aforementioned substituent group Y is used.
As the “acyl group”, a “formyl group”, an “optionally substituted hydrocarbon-carbonyl group”, an “optionally substituted heterocyclyl-carbonyl group”, an “optionally substituted carbamoyl group”, an “optionally substituted sulfonyl group”, an “optionally substituted sulfamoyl group”, an “optionally esterified carboxyl group” and the like for the aforementioned substituent group Y are used.
As R2, an optionally substituted hydrocarbon group, an optionally substituted heterocyclic group and the like are preferable. For example,
(i) a C1-8 alkyl group (preferably a C1-6 alkyl group) (e.g., a tert-butyl group),
(ii) a C2-8 alkenyl group (e.g., a C2-6 alkenyl group such as a propenyl group and the like),
(iii) a C3-8 cycloalkyl group (e.g., a cyclohexyl group),
(iv) a hydroxy group (e.g., an ethyloxy group, a propyloxy group, a propenyloxy group, a benzyloxy group) optionally substituted by C1-8 alkyl (preferably C1-6 alkyl), C2-8 alkenyl (preferably C2-6 alkenyl) or C6-18 aryl-C1-4 alkyl (preferably phenyl-C1-4 alkyl),(v) a C6-18 aryl group (preferably a phenyl group) optionally substituted by a halogen atom, an optionally halogenated C1-8 alkyl (preferably optionally halogenated C1-6 alkyl) or C1-8 alkoxy (preferably C1-6 alkoxy) (e.g., a phenyl group, a trifluoromethylphenyl group, a fluorophenyl group, a difluorophenyl group, a methoxyphenyl group, a chlorophenyl group),(vi) a C6-18 aryl-C1-4 alkyl group (preferably a phenyl-C1-4 alkyl group) (e.g., a benzyl group),(vii) a 4- to 7-membered (preferably 5- or 6-membered) aromatic monocyclic heterocyclic group (e.g., a thienyl group, a furyl group) containing, besides carbon atom, 1 to 3 heteroatoms selected from a nitrogen atom, an oxygen atom and a sulfur atom,(vii) a 4- to 7-membered (preferably 5- or 6-membered) non-aromatic heterocyclic group (e.g., a tetrahydropyranyl group) containing, besides carbon atom, 1 to 3 heteroatoms selected from a nitrogen atom, an oxygen atom and a sulfur atom and the like are preferably used. Among these, a C6-18 aryl group (e.g., phenyl group, trifluoromethylphenyl group, fluorophenyl group, difluorophenyl group, methoxyphenyl group, chlorophenyl group) optionally substituted by a halogen atom, an optionally halogenated C1-8 alkyl or C1-8 alkoxy, and the like are preferable.
R1 is (1) CON(R4)R4′, wherein R4 and R4′ are hydrogen or optionally substituted C1-C6 aliphatic, or (2) an optionally substituted 5-membered aromatic heterocyclic group containing 2 to 4 nitrogen atoms besides carbon atom, which is bonded via a carbon atom; (2) an optionally substituted 5-membered aromatic heterocyclic group containing 2 to 4 nitrogen atoms besides carbon atom, which is bonded via a carbon atom or (3) an optionally substituted 5-membered aromatic heterocyclic group containing 1 to 3 nitrogen atoms besides carbon atom and further containing one oxygen atom or sulfur atom, which is bonded via a carbon atom.
As R1, (1) an optionally substituted 5-membered aromatic heterocyclic group containing 2 to 4 nitrogen atoms besides carbon atom, which is bonded via a carbon atom or (2) an optionally substituted 5-membered aromatic heterocyclic group containing 1 to 3 nitrogen atoms besides carbon atom and further containing one oxygen atom or sulfur atom, which is bonded via a carbon atom is preferable.
However, when R1 is an optionally substituted thiazolyl group and HY is an optionally substituted thiazolyl group, the optionally substituted thiazolyl group for HY is a group represented by
wherein Ra is a hydrogen atom, an alkyl group or a halogen atom,Rb is (i) a hydrogen atom, (ii) an optionally substituted hydrocarbon-carbonyl group, (iii) an optionally substituted heterocyclyl-carbonyl group, (iv) an optionally substituted carbamoyl group, (v) an optionally substituted alkoxycarbonyl group, (vi) an optionally substituted hydrocarbon-sulfonyl group, (vii) an optionally substituted heterocyclyl-sulfonyl group, (viii) an optionally substituted sulfamoyl group, (ix) an optionally substituted hydrocarbon group or (x) an optionally substituted heterocyclic group.
Examples of the “5-membered aromatic heterocyclic group containing 2 to 4 nitrogen atoms besides carbon atom, which is bonded via a carbon atom” include imidazolyl (e.g., 1-imidazolyl, 2-imidazolyl, 4-imidazolyl, 5-imidazolyl), pyrazolyl (e.g., 1-pyrazolyl, 3-pyrazolyl, 4-pyrazolyl), triazolyl (e.g., 1,2,4-triazol-1-yl, 1,2,4-triazol-3-yl, 1,2,3-triazol-1-yl, 1,2,3-triazol-2-yl, 1,2,3-triazol-4-yl), tetrazolyl (e.g., tetrazol-1-yl, tetrazol-5-yl) and the like. Particularly, triazolyl (e.g., 1,2,4-triazol-1-yl, 1,2,4-triazol-3-yl, 1,2,3-triazol-1-yl, 1,2,3-triazol-2-yl, 1,2,3-triazol-4-yl) is preferable.
As the substituent of the “5-membered aromatic heterocyclic group containing 2 to 4 nitrogen atoms besides carbon atom, which is bonded via a carbon atom”, a group selected from the aforementioned substituent group X is used. Particularly, C1-8 alkyl (preferably, C1-6 alkyl such as methyl and the like) and the like are preferable.
As the “5-membered aromatic heterocyclic group containing 1 to 3 nitrogen atoms besides carbon atom and further containing one oxygen atom or sulfur atom, which is bonded via a carbon atom”, thiazolyl (e.g., 2-thiazolyl, 4-thiazolyl, 5-thiazolyl), isothiazolyl (e.g., 3-isothiazolyl, 4-isothiazolyl, 5-isothiazolyl), oxazolyl (e.g., 2-oxazolyl, 4-oxazolyl, 5-oxazolyl), isoxazolyl (e.g., 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl), oxadiazolyl (e.g., 1,2,4-oxadiazol-5-yl, 1,3,4-oxadiazol-2-yl), thiadiazolyl (e.g., 1,3,4-thiadiazol-2-yl) and the like are used.
As the substituent of the “5-membered aromatic heterocyclic group containing 1 to 3 nitrogen atoms besides carbon atom and further containing one oxygen atom or sulfur atom, which is bonded via a carbon atom”, a group selected from the aforementioned substituent group X is used. Particularly, C1-8 alkyl (preferably, C1-6 alkyl such as methyl and the like) and the like are preferable.
As R1, triazolyl (e.g., 1,2,4-triazol-1-yl, 1,2,4-triazol-3-yl, 1,2,3-triazol-1-yl, 1,2,3-triazol-2-yl, 1,2,3-triazol-4-yl) optionally substituted by C1-8 alkyl (preferably, C1-6 alkyl such as methyl and the like) and the like are preferable.
R4 and R4′ are respectively hydrogen, —Z1—R5, optionally substituted C1-6 aliphatic, or optionally substituted 3-10-membered cycloaliphatic, wherein Z1 is selected from an optionally substituted C1-3 alkylene chain, —S(O)—, —S(O)2—, —C(O)—, —CO2—, —C(O)NR4a—, or —S(O)2NR4a—, wherein R4a is hydrogen or an optionally substituted C1-4 aliphatic, and R5 is an optionally substituted group selected from C1-6 aliphatic, 3-10-membered cycloaliphatic, 4-10-membered heterocyclyl having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur, 6-10-membered aryl, or 5-10-membered heteroaryl having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur.
Examples of “optionally substituted C1-6 aliphatic group” include C1-6 alkyl (e.g. methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl), C2-6 alkenyl group (e.g. ethenyl, 1-propenyl, 2-propenyl, 2-methyl-1-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 3-methyl-2-butenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 4-methyl-3-pentenyl, 1-hexenyl, 3-hexenyl, 5-hexenyl) or C2-6 alkynyl group (e.g. ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 3-butynyl, 1-pentynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl, 1-hexynyl, 2-hexynyl, 3-hexynyl, 4-hexynyl, 5-hexynyl) each of which is optionally substituted by a group selected from the aforementioned substituent group X.
Examples of “optionally substituted 3-10-membered cycloaliphatic group” includes C3-10 cycloalkyl group (e.g. cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl) optionally substituted by a group selected from the aforementioned substituent group X.
Examples of “optionally substituted C1-3 alkylene chain” include methylene, ethylene or propylene each of which is optionally substituted by a group selected from the aforementioned substituent group X.
Examples of “optionally substituted C1-4 aliphatic group” include C1-4 alkyl (e.g. methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl), C2-4 alkenyl group (e.g. ethenyl, 1-propenyl, 2-propenyl, 2-methyl-1-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 3-methyl-2-butenyl) or C2-4 alkynyl group (e.g. ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 3-butynyl) each of which is optionally substituted by a group selected from the aforementioned substituent group X.
Examples of “optionally substituted 4-10-membered heterocyclyl group having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur” include the 4- to 7-membered (preferably 5- or 6-membered) monocyclic non-aromatic heterocyclic group containing, as a ring constituting atom besides carbon atom, 1 to 4 heteroatoms selected from an oxygen atom, a sulfur atom and a nitrogen atom mentioned above or the fused non-aromatic heterocyclic group derived from a fused ring wherein a ring corresponding to such 4- to 7-membered monocyclic non-aromatic heterocyclic group, and 1 or 2 rings selected from a 5- or 6-membered heterocycle containing 1 or 2 nitrogen atoms, a 5-membered heterocycle containing one sulfur atom and a benzene ring are condensed each of which is optionally substituted by a group selected from the aforementioned substituent group X.
Examples of “optionally substituted 6-10-membered aryl group” include phenyl, naphthyl, anthryl, phenanthryl, acenaphthylenyl, biphenylyl and the like, especially phenyl, each of which is optionally substituted by a group selected from the aforementioned substituent group X.
Examples of “optionally substituted 5-10-membered heteroaryl group having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur” include the 4- to 7-membered (preferably 5- or 6-membered) monocyclic aromatic heterocyclic group containing, as a ring constituting atom besides carbon atom, 1 to 4 heteroatoms selected from an oxygen atom, a sulfur atom and a nitrogen atom mentioned above or the fused aromatic heterocyclic group derived from a fused ring wherein a ring corresponding to such 4- to 7-membered monocyclic aromatic heterocyclic group, and 1 or 2 rings selected from a 5- or 6-membered aromatic heterocycle containing 1 or 2 nitrogen atoms, a 5-membered aromatic heterocycle containing one sulfur atom and a benzene ring are condensed mentioned above each of which is optionally substituted by a group selected from the aforementioned substituent group X.
As R4 and R4′, hydrogen is preferable.
As R4a, hydrogen or C1-4 alkyl is preferable.
R6 is hydrogen or optionally substituted C1-4alkyl.
As the substituent of the “C1-4 alkyl”, a group selected from the aforementioned substituent group X is used.
As R10d, hydrogen or C1-6 alkyl such as methyl and the like are preferable.
R10e is H, hydroxy, C1-6alkyl, C1-6 alkoxy optionally substituted by a group selected from hydroxy, C1-6 alkyl-carbonylamino and amino-C1-6 alkyl-carbonylamino, C6-18 aryl-C1-4alkyl-oxy, 4- to 7-membered monocyclic aromatic heterocyclyl-C1-4 alkyl-oxy containing, as a ring constituting atom besides carbon atom, 1 to 4 heteroatoms selected from an oxygen atom, a sulfur atom and a nitrogen atom optionally substituted by C1-6 alkyl optionally substituted by halogen and 4- to 7-membered monocyclic non-aromatic heterocyclyl-C1-4 alkyl-oxy containing, as a ring constituting atom besides carbon atom, 1 to 4 heteroatoms selected from an oxygen atom, a sulfur atom and a nitrogen atom optionally substituted by a group selected from halogen, C1-6 alkyl, C1-6 alkylsulfonyloxy and C1-6 alkyl-carbonyl optionally substituted by hydroxyl.
For the compound (I-A-i), (I-A-ii), (II-A-ii) or (I-B-i), any combinations of preferable groups for each symbol mentioned above are preferably used.
As the compound (I-A-i), (I-A-ii) or (I-B-i), the following compound is preferable.
(i) The compound (I-A-i), (I-A-ii) or (I-B-i), especially (I-A-i) or (I-A-ii) wherein,
HY is (i) an optionally substituted group represented by
wherein A is a cyclic group and X is CH or N, or
(ii) a pyridyl group, a pyrimidinyl group, a pyrazolyl group, a thiazolyl group, an oxazolyl group, an imidazolyl group, a triazolyl group, an isothiazolyl group or a pyridazinyl group, each of which is optionally substituted;
R2 is an optionally substituted aryl group optionally substituted by substituents selected from substituent group X, a C6-18 aryl-C1-4 alkyl group optionally substituted by substituents selected from substituent group X, a 4- to 7-membered (preferably 5- or 6-membered) monocyclic aromatic heterocyclic group containing, as a ring constituting atom besides carbon atom, 1 to 4 heteroatoms selected from an oxygen atom, a sulfur atom and a nitrogen atom, or a group derived from a fused ring wherein a ring corresponding to such 4- to 7-membered monocyclic aromatic heterocyclic group, and 1 or 2 rings selected from a 5- or 6-membered aromatic heterocycle containing 1 or 2 nitrogen atoms, a 5-membered aromatic heterocycle containing one sulfur atom and a benzene ring are condensed,
R1 is (1) an optionally substituted 5-membered aromatic heterocyclic group containing 2 to 4 nitrogen atoms besides carbon atom, which is bonded via a carbon atom or (2) an optionally substituted 5-membered aromatic heterocyclic group containing 1 to 3 nitrogen atoms besides carbon atom and further containing one oxygen atom or sulfur atom.
(ii) The compound (I-A-i), (I-A-ii) or (I-B-i), especially (I-A-i) or (I-A-ii) wherein,
HY is
(i) a group represented by
particularly, a group represented by
optionally substituted by the above-mentioned substituent(s), particularly, (1) hydroxy, (2) C1-6 alkyl such as methyl and the like which is optionally substituted by 4- to 7-membered (preferably 5- or 6-membered) monocyclic aromatic heterocyclyl-carbonyl-amino or C1-6 alkylcarbonylamino optionally substituted by amino containing, as a ring constituting atom besides carbon atom, 1 to 4 heteroatoms selected from an oxygen atom, a sulfur atom and a nitrogen atom, (3) C1-6 alkoxy optionally substituted by hydroxy, (4) C6-18 aryl-C1-4 alkyl-oxy (e.g., benzyloxy), (5) 4- to 7-membered (preferably 5- or 6-membered) monocyclic aromatic heterocyclyl-C1-4 alkyl-oxy containing, as a ring constituting atom besides carbon atom, 1 to 4 heteroatoms selected from an oxygen atom, a sulfur atom and a nitrogen atom which is optionally substituted by C1-6 alkyl optionally substituted by halogen, (6) 4- to 7-membered (preferably 5- or 6-membered) monocyclic non-aromatic heterocyclyl-C1-4alkyl-oxy (e.g., morpholinylethyloxy, piperidinylethyloxy) containing, as a ring constituting atom besides carbon atom, 1 to 4 heteroatoms selected from an oxygen atom, a sulfur atom and a nitrogen atom and the like (e.g., hydroxy, C1-6 alkyl such as methyl and the like) as well as (7) halogen, (8) C2-6 alkenyl, (9)C3-8 cycloalkyl, (10) C6-18 aryl optionally substituted by C1-6 alkoxy or halogen, (11) 4- to 7-membered (preferably 5- or 6-membered) monocyclic aromatic heterocyclyl containing, as a ring constituting atom besides carbon atom, 1 to 4 heteroatoms selected from an oxygen atom, a sulfur atom and a nitrogen atom which is optionally substituted by C1-6 alkyl, (12) 4- to 7-membered (preferably 5- or 6-membered) monocyclic non-aromatic heterocyclyl containing, as a ring constituting atom besides carbon atom, 1 to 4 heteroatoms selected from an oxygen atom, a sulfur atom and a nitrogen atom which is optionally substituted by C1-6 alkyl,
(ii) a group represented by
optionally substituted by the above-mentioned substituent(s), particularly, (1) hydroxy, (2) C1-6 alkyl such as methyl and the like which is optionally substituted by 4- to 7-membered (preferably 5- or 6-membered) monocyclic aromatic heterocyclyl-carbonyl-amino or C1-6 alkylcarbonylamino optionally substituted by amino containing, as a ring constituting atom besides carbon atom, 1 to 4 heteroatoms selected from an oxygen atom, a sulfur atom and a nitrogen atom, (3) C1-6 alkoxy optionally substituted by hydroxy, (4) C6-18 aryl-C1-4 alkyl-oxy (e.g., benzyloxy), (5) 4- to 7-membered (preferably 5- or 6-membered) monocyclic aromatic heterocyclyl-C1-4 alkyl-oxy containing, as a ring constituting atom besides carbon atom, 1 to 4 heteroatoms selected from an oxygen atom, a sulfur atom and a nitrogen atom, which is optionally substituted by C1-6 alkyl optionally substituted by halogen (6) 4- to 7-membered (preferably 5- or 6-membered) monocyclic non-aromatic heterocyclyl-C1-4alkyl-oxy (e.g., morpholinylethyloxy, piperidinylethyloxy) containing, as a ring constituting atom besides carbon atom, 1 to 4 heteroatoms selected from an oxygen atom, a sulfur atom and a nitrogen atom and the like (e.g., hydroxy, C1-6 alkyl such as methyl and the like) as well as (7) halogen, (8) C2-6 alkenyl, (9)C3-8 cycloalkyl, (10) C6-18 aryl optionally substituted by C1-6 alkoxy or halogen, (11) 4- to 7-membered (preferably 5- or 6-membered) monocyclic aromatic heterocyclyl containing, as a ring constituting atom besides carbon atom, 1 to 4 heteroatoms selected from an oxygen atom, a sulfur atom and a nitrogen atom which is optionally substituted by C1-6 alkyl, (12) 4- to 7-membered (preferably 5- or 6-membered) monocyclic non-aromatic heterocyclyl containing, as a ring constituting atom besides carbon atom, 1 to 4 heteroatoms selected from an oxygen atom, a sulfur atom and a nitrogen atom which is optionally substituted by C1-6 alkyl, or
(iii) a group represented by

wherein Ra is a hydrogen atom, a halogen atom (e.g., chlorine atom), a C1-6 alkyl group such as methyl, ethyl, propyl and the like,
Rb is (1) a hydrogen atom, (2) a C1-8 alkyl-carbonyl group (e.g., C1-6 alkyl-carbonyl group such as acetyl, ethylcarbonyl and the like) optionally substituted by a substituent(s) selected from C6-18 arylthio (e.g., phenylthio), 4- to 7-membered (preferably 5- or 6-membered) monocyclic aromatic heterocyclic group or monocyclic non-aromatic heterocyclic group (e.g., morpholinyl) containing, as a ring constituting atom besides carbon atom, 1 to 4 heteroatoms selected from an oxygen atom, a sulfur atom and a nitrogen atom, and the like, (3) a C3-8 cycloalkyl-carbonyl group (e.g., cyclopropylcarbonyl) and the like,
Rc is a hydrogen atom, a C1-6 alkyl group such as methyl, ethyl, propyl and the like, and
Rd is (i) a hydrogen atom, (ii) a C1-6 alkyl group such as methyl, ethyl, propyl and the like, or (iii) an optionally substituted heterocyclic group represented by
especially,wherein Ra, Rb and Rc are as defined above, and Rd is hydrogen atom, a C1-6 alkyl group such as methyl, ethyl, propyl and the like, especially HY is(i) a group represented by
optionally substituted by the above-mentioned substituent(s), particularly, (1) hydroxy, (2) C1-6 alkyl such as methyl and the like which is optionally substituted by 4- to 7-membered (preferably 5- or 6-membered) monocyclic aromatic heterocyclyl-carbonyl-amino or C1-6 alkylcarbonylamino optionally substituted by amino containing, as a ring constituting atom besides carbon atom, 1 to 4 heteroatoms selected from an oxygen atom, a sulfur atom and a nitrogen atom, (3) C1-6 alkoxy optionally substituted by hydroxy, (4) C6-18 aryl-C1-4alkyl-oxy (e.g., benzyloxy), (5) 4- to 7-membered (preferably 5- or 6-membered) monocyclic aromatic heterocyclyl-C1-4 alkyl-oxy containing, as a ring constituting atom besides carbon atom, 1 to 4 heteroatoms selected from an oxygen atom, a sulfur atom and a nitrogen atom, which is optionally substituted by C1-6 alkyl optionally substituted by halogen (6) 4- to 7-membered (preferably 5- or 6-membered) monocyclic non-aromatic heterocyclyl-C1-4alkyl-oxy (e.g., morpholinylethyloxy, piperidinylethyloxy) containing, as a ring constituting atom besides carbon atom, 1 to 4 heteroatoms selected from an oxygen atom, a sulfur atom and a nitrogen atom and the like (e.g., hydroxy, C1-6 alkyl such as methyl and the like) as well as (7) halogen, (8) C2-6 alkenyl, (9) C3-8 cycloalkyl, (10) C6-18 aryl optionally substituted by C1-6 alkoxy or halogen, (11) 4- to 7-membered (preferably 5- or 6-membered) monocyclic aromatic heterocyclyl containing, as a ring constituting atom besides carbon atom, 1 to 4 heteroatoms selected from an oxygen atom, a sulfur atom and a nitrogen atom which is optionally substituted by C1-6 alkyl, (12) 4- to 7-membered (preferably 5- or 6-membered) monocyclic non-aromatic heterocyclyl containing, as a ring constituting atom besides carbon atom, 1 to 4 heteroatoms selected from an oxygen atom, a sulfur atom and a nitrogen atom which is optionally substituted by C1-6 alkyl, or(iii) a group represented by
wherein Ra is a hydrogen atom, a halogen atom (e.g., chlorine atom), a C1-6 alkyl group such as methyl, ethyl, propyl and the like,
Rb is (1) a hydrogen atom, (2) a C1-8 alkyl-carbonyl group (e.g., C1-6 alkyl-carbonyl group such as acetyl, ethylcarbonyl and the like) optionally substituted by a substituent(s) selected from C6-18 arylthio (e.g., phenylthio), 4- to 7-membered (preferably 5- or 6-membered) monocyclic aromatic heterocyclic group or monocyclic non-aromatic heterocyclic group (e.g., morpholinyl) containing, as a ring constituting atom besides carbon atom, 1 to 4 heteroatoms selected from an oxygen atom, a sulfur atom and a nitrogen atom, and the like, (3) a C3-8 cycloalkyl-carbonyl group (e.g., cyclopropylcarbonyl) and the like,
Rc is a hydrogen atom, a C1-6 alkyl group such as methyl, ethyl, propyl and the like, and Rd is (i) a hydrogen atom, (ii) a C1-6 alkyl group such as methyl, ethyl, propyl and the like, or (iii) an optionally substituted heterocyclic group represented by
especially,wherein Ra, Rb and Rc are as defined above, and Rd is hydrogen atom, a C1-6 alkyl group such as methyl, ethyl, propyl and the like,R2 is(i) a C1-8 alkyl group (preferably a C1-6 alkyl group) (e.g., a tert-butyl group),(ii) a C2-8 alkenyl group (e.g., a C2-6 alkenyl group such as a propenyl group and the like),(iii) a C3-8 cycloalkyl group (e.g., a cyclohexyl group),(iv) a hydroxy group (e.g., an ethyloxy group, a propyloxy group, a propenyloxy group, a benzyloxy group) optionally substituted by C1-8 alkyl (preferably C1-6 alkyl), C2-8 alkenyl (preferably C2-6 alkenyl) or C6-18 aryl-Cm alkyl (preferably phenyl-Cm alkyl),(v) a C6-18 aryl group (preferably a phenyl group) optionally substituted by a halogen atom, an optionally halogenated C1-8 alkyl (preferably optionally halogenated C1-6 alkyl) or C1-8 alkoxy (preferably C1-6 alkoxy) (e.g., a phenyl group, a trifluoromethylphenyl group, a fluorophenyl group, a difluorophenyl group, a methoxyphenyl group, a chlorophenyl group),(vi) a C6-18 aryl-C1-4 alkyl group (preferably a phenyl-C1-4 alkyl group) (e.g., a benzyl group),(vii) a 4- to 7-membered (preferably 5- or 6-membered) aromatic monocyclic heterocyclic group (e.g., a thienyl group, a furyl group) containing, besides carbon atom, 1 to 3 heteroatoms selected from a nitrogen atom, an oxygen atom and a sulfur atom, or(vii) a 4- to 7-membered (preferably 5- or 6-membered) non-aromatic heterocyclic group (e.g., a tetrahydropyranyl group) containing, besides carbon atom, 1 to 3 heteroatoms selected from a nitrogen atom, an oxygen atom and a sulfur atom and the like are preferably used. Among these, a C6-18 aryl group (e.g., phenyl group, trifluoromethylphenyl group, fluorophenyl group, difluorophenyl group, methoxyphenyl group, chlorophenyl group) optionally substituted by a halogen atom, an optionally halogenated C1-8 alkyl or C1-8 alkoxy, especially,(i) a C6-18 aryl group (preferably a phenyl group) optionally substituted by a halogen atom, an optionally halogenated C1-8 alkyl (preferably optionally halogenated C1-6 alkyl) or C1-8 alkoxy (preferably C1-6 alkoxy) (e.g., a phenyl group, a trifluoromethylphenyl group, a fluorophenyl group, a difluorophenyl group, a methoxyphenyl group, a chlorophenyl group), or(ii) a 4- to 7-membered (preferably 5- or 6-membered) aromatic monocyclic heterocyclic group (e.g., a thienyl group, a furyl group) containing, besides carbon atom, 1 to 3 heteroatoms selected from a nitrogen atom, an oxygen atom and a sulfur atom,
R1 is triazolyl (e.g., 1,2,4-triazol-1-yl, 1,2,4-triazol-3-yl, 1,2,3-triazol-1-yl, 1,2,3-triazol-2-yl, 1,2,3-triazol-4-yl) optionally substituted by C1-8 alkyl (preferably, C1-6 alkyl such as methyl and the like).
For the above mentioned compounds, any combinations of preferable groups for each symbol mentioned above are preferably used.
As a salt of compound represented by the formula (IA), (IB), (I-A-i), (I-A-ii), (I-A-iv), (I-B-i), (II-A), (II-A-i), (II-A-ii), for example, metal salts, ammonium salts, salts with organic bases, salts with inorganic acids, salts with organic acids, salts with basic or acidic amino acids and the like can be mentioned. As preferable examples of the metal salt, alkali metal salts such as sodium salt, potassium salt and the like; alkaline earth metal salts such as calcium salt, magnesium salt, barium salt and the like; aluminum salt and the like can be mentioned. As preferable examples of the salts with organic bases, salts with trimethylamine, triethylamine, pyridine, picoline, 2,6-lutidine, ethanolamine, diethanolamine, triethanolamine, tromethamine[tris(hydroxymethyl)methylamine], t-butylamine, cyclohexylamine, dicyclohexylamine, N,N′-dibenzylethylenediamine and the like can be mentioned. As preferable examples of the salts with inorganic acids, salts with hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid and the like can be mentioned. As preferable examples of the salts with organic acids, salts with formic acid, acetic acid, trifluoroacetic acid, phthalic acid, fumaric acid, oxalic acid, tartaric acid, maleic acid, citric acid, succinic acid, malic acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid and the like can be mentioned. As preferable examples of the salts with basic amino acids, salts with arginine, lysine, ornithine and the like can be mentioned. As preferable examples of the salts with acidic amino acids, salts with aspartic acid, glutamic acid and the like can be mentioned.
Of those, pharmaceutically acceptable salts are preferable. For example, when a compound has an acidic functional group therein, salts with inorganic bases such as alkali metal salts (e.g., sodium salt, potassium salt and the like), alkaline earth metal salts (e.g., calcium salt, magnesium salt, barium salt and the like) and the like, ammonium salt and the like can be mentioned. When a compound has a basic functional group therein, salts with inorganic acids such as hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid and the like, and salts with organic acids such as acetic acid, phthalic acid, fumaric acid, oxalic acid, tartaric acid, maleic acid, citric acid, succinic acid, methanesulfonic acid, p-toluenesulfonic acid and the like can be mentioned.
4 General Synthetic Methods and Intermediates:
The compounds of the present invention can be prepared by methods known to one of ordinary skill in the art and/or by reference to the schemes shown below and the synthetic examples that follow. Exemplary synthetic routes are set forth in Schemes 1-52 below, and in the Examples.
In methods defined below X represents halogen (Br, I or Cl), P is Hy itself or a substituent convertible to Hy by applying a generally known method, Wa is R2 itself or a substituent convertible to R2 by applying a generally known method and Q is R1 itself or a substituent convertible to R1 by applying a generally known method.
Examples of the solvent for the below-mentioned reactions include, but are not limited to halogenated hydrocarbons such as dichloromethane, chloroform, carbon tetrachloride, 1,2-dichloroethane and the like, aromatic hydrocarbons such as benzene, toluene, xylene and the like, alcohols such as methanol, ethanol, isopropanol, tert-butanol, phenol and the like, ethers such as diethyl ether, tetrahydrofuran, dioxane, DME and the like, acetone, acetonitrile, ethyl acetate, N,N-dimethylformamide, N,N-dimethylacetamide, 1-methyl-2-pyrrolidone, dimethyl sulfoxide, hexamethylphosphoramide, water or a mixed solvent thereof and the like.
One of ordinary skill in the art will recognise that numerous variations in reaction conditions including variations in solvent, reagents, catalysts, reaction temperatures and times are possible for each of the reactions described. Variation of order of synthetic steps and alternative synthetic routes are also possible.
In many cases, synthesis can be started from commercially available thiophene/thiazole analogs to prepare target compounds. In some cases, specially functionalized thiophene/thiazole analogs can be prepared by the procedures described in Schemes 1-4.

Scheme 1 above shows a procedure to prepare compounds of formula v. Condensation of nitriles i with 2,5-dihydroxy-1,4-dithiane can be accomplished using reported procedure (C. E. Stephens et al. Bioorg. Med. Chem., 2001, 9, 1123-1132, Method A). Aminothiophenes ii are then protected with an appropriate protecting group, for example Boc using standard conditions, such as Boc anhydride, DMAP, dioxane (Method B). Halogenation of protected thiophenes iii is achieved using a suitable reagent, for example NBS in DCM to afford halides of formula iv (Method C), that can be converted into compounds of formula v by a combination of generally known functional group conversion reactions described below.
Alternatively, reverse type of thiophene analogs vi can be also prepared using functional group transformations described below.

Suitably functionalized 4-hydroxyl thiophenes can be prepared according to the published procedure such as M. D. Mullican, et al., J. Med. Chem., 1991, 34, 2186-2194. For example, scheme 2 describes a general procedure for preparing 4-hydroxythiophenes of formula x. Beta-ketoesters vii are treated with thiols, such as methyl thioglycolate, viii in the presence of suitable acid, such as HCl in ethanol (Method D), to afford dithio-ketal ix, which is then treated with an appropriate base, like sodium ethoxide in a suitable solvent, for example ethanol to give 4-hydroxythiophenes of formula x (Method E). These 4-hydroxythiophenes can be convertated to target compounds v according to the procedures described below.

Scheme 3 above shows a general route for the synthesis of compounds of formula xiii and xvi.
Thioamides xi or thioureas (When P=NHR) are treated with alpha-halogenated carbonyl compounds xii in a suitable solvent, such as isopropanol at elevated temperature to give thiazoles xiii. (Method F). When P=NH2, 2-aminothiazoles xiii that are obtained can be then subjected to Sandmeyer reaction to afford 2-halothiazoles xxxi (P=X), which can be used for further functional transformations described below. A conversion reaction from xiii to compounds xiv can be performed, for example, by a combination of generally known functional group conversion reactions shown below. If alfa-halogenated carbonyl compound is suitably selected, i.e. xv, reverse type thiazole analogs xvi and xvii can be also prepared using well known organic functional group transformation reactions describing below.
As shown in scheme 4 above, thioamides xi can be condensed with alfa-halogenated esters in a similar manner as reported by Rzasa, R. M. et al, Bioorg. Med. Chem. 2007, 15, 6574 to obtain 4-hydroxythiazole derivatives xviii. Reaction can be carried out in a suitable solvent, such as ethanol in the presence of an appropriate base, like pyridine under elevated temperature (Method G).
Schemes 5-19 describe procedures for basic functional group transformations on the thiophene/thiazole central core scaffolds.
In the schemes 5-8, general functional group transformation procedures for introduction of Hy group are described.

Scheme 5 describes the procedure for the introduction of Hy to 3-cyanothiophene analogs by a known functional group transformation reaction.
As shown in Scheme 5, sulfones of formula xix (synthetic examples given in Mansanet et al, WO 2005070916) are treated with amines, preferably such as the R′ group can be later deprotected, for example 2,4-dimethoxybenzylamine in a suitable solvent, such as THF at elevated temperature (Method H) to give XX.
Deprotection of R′ group is carried out using a standard procedure, in the case of dimethoxybenzyl group with an acid, such as TFA in DCM to afford amines xxi (Method I).
Amines xxi are then subjected to Sandmeyer reaction using appropriate reagents, such as methylene iodide and amyl nitrite in ACN (Method J).
The resulting halogenated thiophenes xxii can be coupled with aryl stannanes under suitable conditions, for example Pd(PPh3)4, CuI, LiCl in a suitable solvent, such as dioxane at elevated temperature to give compounds of formula xxiii (Method K). Alternatively, boronic acids or esters can be used for such coupling reactions, for example Pd(PPh3)4, Na2CO3, DME/water, elevated temperature or microwave irradiation (Method L).
A conversion reaction from xxiii to compounds xxiv can be performed, for example, by a combination of generally known functional group conversion reactions shown below.

Scheme 6 above shows a general route for introducing Hy to unsubstituted 2-position of thiophene core.
2-unsubstituted thiophenes xxv can be treated with suitable base, such as n-BuLi in THF at low temperature, to produce lithiated thiophene intermediates xxvi (Method M). The intermediate organolithium species can be quenched with halogen molecule, for example iodine in a suitable solvent, such as THF to afford halogenated compounds of formula xxvii (Method N). Halides xxvii can be coupled with aryl stannanes under suitable conditions, for example Pd(PPh3)4, CuI, LiCl in a suitable solvent, such as dioxane at elevated temperature to give compounds of formula xxviii (Method K), or boronic acids or esters. with an appropriate catalyst, for example Pd(PPh3)4, in the presence of a suitable base, such as sodium carbonate in DME-water mixture at elevated temperature (Method L) to afford compounds of formula xxviii.
Alternatively, lithium intermediates xxvi can be transformed to stannanes by quenching with suitable tin halide, such as tributyltin chloride (Method O). Stannanes xxix are then coupled with aryl halides, triflates, or mesylates using appropriate conditions, such as Pd(PPh3)4, CuI, LiCl in a suitable solvent, such as dioxane at elevated temperature to give compounds of formula xxviii (Method K). A conversion reaction from xxviii to compounds v can be performed, for example, by a combination of generally known functional group conversion reactions shown below.

Scheme 7 above shows a general route for introducing Hy to 2-position of thiazole core scaffold.
Halogenated thiazoles xxxi, which can be available by the procedure described in scheme 3, can coupled with suitable partners, such as boronic acids, stannanes, etc under standard Suzuki conditions, such as Pd(PPh3)4, Na2CO3, DME/water, elevated temperature or microwave irradiation (Method L), or standard Stille conditions, such as Pd(PPh3)4, CuI, LiCl, dioxane at elevated temperature (Method K) to afford compounds of formula xiii.
A conversion reaction from xiii to compounds xiv can be performed, for example, by a combination of generally known functional group conversion reactions shown below.

As shown in Scheme 8, cross-coupling reaction described in scheme 7 can be regioselectively applied to the 2,4-dihalogenated thiazole derivatives xxxii. Thus, stepwise palladium mediated Stille/Suzuki cross coupling reactions afford suitably functionalized thiazole derivatives xiii. For example, 2,4-dihalothiazoles xxxii are treated with stannanes under standard Stille conditions, such as Pd(PPh3)4, CuI, LiCl, dioxane at elevated temperature (Method K) to afford intermediates xxxiii, that are then treated with organic boronic acids under standard Suzuki conditions, such as Pd(PPh3)4, Na2CO3, DME/water, elevated temperature or microwave irradiation (Method L) to afford compounds of formula xiii.
Schemes 9-21 describe methods for the introduction of R1 and R2 groups.

4-Alkoxythiazoles can be obtained by the conventional alkylation method of 4-hydroxythiazole derivatives obtained in scheme 4.
As shown in scheme 9,4-hydroxythiazoles xviii can be treated with alkyl halides using a suitable base, such as potassium carbonate in a suitable solvent, for example DMF at elevated temperature to afford compounds of formula xxxiv (Method P).

Scheme 10 above shows a general route for introducing halogen functionality onto 4-unsubstituted position of thiophene/thiazole core.
Halogenation of thiophene/thiazoles can be achieved in a similar manner as reported in the literature (Takami et al, Tetrahedron 2004, 60, 6155). For example, xxxv is treated with a generally known halogenating reagent such as bromine or N-bromosuccinimide, in a suitable solvent, such as DCM at elevated temperature to afford compounds of formula xxxvi (Method C).
The halogenated thiazole xxxvi can be used for further functional group transformation shown below.

Scheme 11 above shows general methods for the synthesis of 4-aminothiazole derivatives xxxvii from 4-halogenated thiazoles xxxiii which can be prepared by the procedure described in scheme 10.
Displacement of a halogen group with an amine can be achieved in a similar manner as reported in the literature (J. Med. Chem. 2006, 49, 5769). Treatment of xxxiii with an amine at elevated temperature in a suitable solvent, such as DMF can lead to amines xxxvii (Method Q). If necessary a base, such as sodium carbonate can be added.

As shown in Scheme 12 above, carbon functionality can be introduced by the well known cross-coupling technique from the 4-halogenated thiophenes/thiazoles xxxvi which can be prepared by the procedure described in schemes 8 or 10.
For example, xxxix can be obtained from 4-halogenated thiophenes/thiazoles xxxvi by reaction with an organic boronic acid reagent, or an organic tin reagent in a presence of palladium catalyst, such as Pd(PPh3)4. Suzuki couplings can be performed using a suitable base, such as sodium carbonate in an appropriate solvent, such as DME/water at elevated temperature (Method L), while co-catalyst CuI can be used for Stille coupling reactions, together with LiCl in a suitable solvent, such as dioxane at elevated temperature (Method K).

As shown in Scheme 13 above, sulfur functionality can be introduced to the 4-halogenated thiazole xxxiii by a similar manner as described by Rossignol et al, US2009036467.
Treatment of xxxiii with thiols in the presence of a copper catalyst, like CuI in a suitable solvent, such as DMF with an appropriate base, for example sodium hydroxide at elevated temperature gives thioethers of formula xl (Method R).

As shown in Scheme 14, amine or amide functionality can be introduced by the well known palladium catalyzed amination/amidation reaction, so called Buchwald coupling, to the 4-halogenated thiophenes/thiazoles xxxvi.
For example, halides xxxvi can be treated with amines using an appropriate Pd catalyst, such as Pd2 dba3/BINAP, with a suitable solvent/base combination, for example NaOtBu in toluene at elevated temperature or using microwave irradiation to afford amines of formula xli (Method S). Coupling with amides also can be carried out using a suitable Pd catalyst, for example Pd2 dba3/XantPhos, with a suitable solvent/base combination, like Cs2CO3 in dioxane at elevated temperature or using microwave irradiation to give amides of formula xlii (Method T).

As shown in Scheme 15, 4-hydroxythiazoles or thiophenes xliii can be transformed to various functionalized thiazole/thiophene derivatives via triflate xliv.
For example, compounds xliii can be transformed into triflates xliv, for example using triflic anhydride, with pyridine as base in DCM (Method U). Triflates xliv can be then subjected to coupling reactions with amines, boronic esters, stannanes, or thiols under similar conditions as described for analogous halides in Schemes 11-14 (analogous literature examples include Rzasa, R. et al, Bioorg. Med. Chem. 2007, 15, 6574; Langille, N. F., Org. Lett. 2002, 4, 2485.) to afford compounds of formula xlv.

Scheme 16 above shows a general route for introducing halogene functionality onto unsubstituted 5-position of thiophene/thiazole core scaffold.
Halogenation of 5-unsubstituted thiazoles/thiophenes can be achieved in a similar manner as reported in the literature (Haelmmerle et al, Synlett 2007, 2975). For example, xlvi is treated with a generally known halogenating reagent such as bromine or N-bromosuccinimide in a suitable solvent, such as DCM to afford compounds of formula xlvii (Method C).
The resulting halogenated thiophenes/thiazoles xlvii can be used for the further functional group transformation reaction such as described in scheme 11-14.

Scheme 17 above shows a general route for preparing amide compounds of formula xlix. As shown in Scheme 17, acids xlviii are treated with amines using standard coupling conditions, such as EDCI and HOBt in DCM to afford amides xlix (Method V).
When ammonia is used as an amine source, obtained primary amide derivatives 1 can be very useful intermediates for the construction of azoles as described below.

As shown Scheme 18, 5-amino thiophens/thiazoles Hi can be prepared by the Curtius rearrangement of the thiophene/thiazole carboxylic acid analogs xlviii.
As shown in Scheme 18, acids xlviii are treated with an azide, such as DPPA in a presence of base, like TEA in a suitable solvent, for example t-BuOH at elevated temperature to form intermediate Boc protected amines 11 (Method W), that are deprotected to amines lii using standard deprotection conditions, such as TFA in DCM (Method I).
Amines lii can be then transformed to amides, sulfonamides, ureas, carbamates HU etc using standard conditions.

As shown in scheme 19, amides 1, which can be prepared by the procedure described in scheme 17, are treated with phosphoryl chloride, or similar reagents to form 5-cyano thiophens/thiazoles of formula liv (Method X).

As shown in scheme 20, amides 1, which can be prepared by the procedure described in scheme 17, are treated with a suitable reagent, for example Lawesson's reagent, or P2S5 in a suitable solvent, such as toluene at elevated temperature to afford thioamides of formula Iv (Method Y).

As shown in scheme 21, 5-cyano thiazoles/thiophenes liv, which can be prepared by the procedure described in scheme 19, are treated with a suitable reagent, for example ammonium sulfide in a suitable solvent, such as methanol to afford thioamides of formula Iv (method Z).
In the schemes 22-40, general procedures for the construction of the representative azoles as R1 are described.
Schemes 22-24 are explaining the formation of 1,2,4-triazolyl group as R1.

As shown in Scheme 22, amides l, which can be prepared by the procedure described in scheme 17, can be treated with dimethylformamide-dimethylacetal such as DMFDMA at elevated temperature or under microwave irradiation (Method AA) to give intermediate amidines lvi that are transformed to 1,2,4-triazoles lvii using hydrazine or substituted hydrazines in acetic acid at elevated temperature or under microwave irradiation (Method AB).

As shown in Scheme 23, 1,2,4-triazoles lvii, which can be prepared by the procedure described in scheme 22, are treated with a suitable halogenating agent, like NBS in a suitable solvent, for example tetrachloromethane to afford compounds of formula lviii (Method C).

As shown in Scheme 24, acids xlviii are coupled with cyanamide, for example via an intermediate acid halide in a suitable solvent, such as DCM to acylcyanamides lix (Method AC), that are in turn treated with hydrazine using appropriate conditions, for example acetic acid at elevated temperature to give compounds of formula lx (Method AD).
Scheme 25-33 is explaining the formation of 2-imidazolyl group as R1

As shown in Scheme 25, acids xlviii are treated with Boc protected ethylenediamine using standard coupling conditions, such as EDCI and HOBt in DCM (Method V). Protective group is removed using an appropriate acid, for example TFA in DCM to give amide lxi (Method I). Cyclization of lxi is achieved using suitable conditions, for example POCl3 (Method AE) to form dihydroimidazoles lxii. Dihydroimidazoles lxii can be oxidized to imidazoles lxiii using a suitable oxidative method, for example heating with Magtrieve (Method AF).

Scheme 26 above shows an alternative route for preparing imidazoles of formula lxiii. As shown in Scheme 26, acids xlviii are treated with amines using standard coupling conditions, such as EDCI and HOBt in DCM to afford amides lxv (Method V). Cyclization to imidazoles is achieved through a 3-step one pot process that involves treatment with phosphorus pentachloride and HCl in dioxane to afford carbimidoyl chloride intermediates lxvi, that are then treated with aminoacetaldehyde dimethylacetal followed by HCl in dioxane at elevated temperature to give lxiii (Method AG). When R′=allyl, benzyl or substituted benzyl, it can also serve as a protecting group.

As shown in scheme 27, aldehydes lxvii are condensed with dicarbonyl compounds, such as diketones, ketoaldehydes, or glyoxal with an appropriate ammonia source, such as ammonium acetate, with suitable acid, such as acetic acid in solvent such as methanol to form imidazoles lxiii (Method AH).

As shown in scheme 28, aldehydes of formula lxvii can be treated with alpha, alpha-dihalo-ketones under suitable conditions, such as ammonium hydroxide, sodium acetate in an appropriate solvent, for example methanol and water to afford imidazoles of formula lxiii (Method AI).

As shown in scheme 29, treatment of nitriles liv, which can be prepared by the procedure described in scheme 19, with LiHMDS in a suitable solvent mixture, such as THF/ether/hexane gives amidines of formula lxviii (Method AJ) that can be treated with haloketones in the presence of a suitable base, such as potassium carbonate in an appropriate solvent, such as DCM under elevated temperature to give imidazoles of general formula lxiii (Method AK).

As shown in scheme 30, treatment of thioamides lv, which can be prepared by the procedure described in scheme 20 or 21, with methyl iodide affords imidothioate intermediates lxix (Method AL), which are then treated with optionally substituted aminoacetaldehyde dimethyl acetal in a suitable solvent, like acetic acid at elevated temperature to afford intermediate amidines lxx (Method AM). Amidines lxx are then treated with an acid, such as aqueous HCl and a suitable co-solvent, like ethanol at elevated temperature to give imidazoles of formula lxiii (Method AN).

As shown in scheme 31, treatment of amides 1, which can be prepared by the procedure described in scheme 17, with an alkylating agent, such as Meerwein's reagent in DCM (Method AO) gives iminoesters lxxi, which are then treated with diamines using appropriate conditions, for example ethanol at elevated temperature (Method AP). Formed dihydroimidazoles lxii can be then oxidized in a same manner as in Method AF described in Scheme 25, or when R7 is appropriate leaving group, elimination can be carried out using a base, such as DBU in DCM (Method AQ).

As shown in Scheme 32, acids xlviii are transformed to ketones lxxii using a suitable synthetic sequence, for example through a coupling with N,O-dimethylhydroxylamine and subsequent treatment of the resulting Weinreb amides with alkyllithium or Grignard reagents in a suitable solvent, like THF (Method AR).
Ketones lxxii are then halogenated with a suitable reagent, such as bromine or NBS in an appropriate solvent, like DCM (Method C) to form alpha-halogenated ketones lxxiii (X=halogen). Alternatively, treatment of ketones lxxii with a suitable oxidative sulfonylating agent, like hydroxy(tosyloxy)iodobenzene using suitable conditions, for example heating in acetonitrile (Method AS) affords sulfonyl esters of formula lxxiii (X=OSO2R).
Treatment of Mill with amidine reagents in the presence of a suitable base, like potassium carbonate in a suitable solvent, such as THF-water mixture at elevated temperature or microwave irradiation affords the final imidazoles lxxiv (Method AT). Alternatively, compounds lxxiii can be treated with large excess of amides, such as formamide using microwave irradiation to afford imidazoles lxxiv (Method AU).

As shown in scheme 33, treatment of nitriles liv, which can be prepared by the procedure described in scheme 19, with isocyanates in the presence of a suitable base, such as tOBuK, in a suitable solvent, for example THF gives imidazoles of formula lxxiv. (Method AV).
Schemes 34 and 35 describe the procedures for introducing pyrazolyl group.

As shown in Scheme 34, ketones lxxii, which can be prepared by the procedure describing in scheme 32, are treated with DMFDMA to afford an intermediate enamines (Method AA) followed by reaction with substituted hydrazine, or hydrazine hydrate in a suitable solvent, for example acetic acid to give pyrazoles lxxv (Method AB).

As shown in Scheme 35, halides xlvii which can be prepared by the procedure described in scheme 16, are treated with pyrrol boronic acid or ester lxxvi, in the presence of a suitable catalyst, for example Pd(PPh3)4, using a base, such as cesium carbonate in a suitable solvent, like dioxane-water mixture at elevated temperature to afford pyrazoles of formula lxxvii (Method L).

As shown in Scheme 36, alkynes lxxviii, which can be prepared by the known Stille- or Sonogashira-coupling reaction of halide xlvii and appropriate alkyne derivative, are treated with azides, inorganic or organic a suitable solvent, such as dioxane at elevated temperature to afford triazoles of formula lxxix (Method AW).

As shown in Scheme 37, amides l, which can be prepared by the procedure described in scheme 17, are treated with an azide source, for example sodium azide using a suitable Lewis acid, for example silicon tetrachloride in an appropriate solvent, such as acetonitrile to give tetrazoles lxxx (Method AX).

As shown in scheme 38, thioamides lv, which can be prepared by the procedure described in scheme 20 or 21, are treated with substituted bromoacetaldehyde dimethyl acetals to afford thiazoles of formula lxxxi (Method AY).

As shown in scheme 39, alpha-halogenated ketones lxxiii, which can be prepared by the procedure described in scheme 32, are treated with formamide under elevated temperature or microwave irradiation to afford the final 4-oxazoles lxxxii (Method AZ).

As shown in scheme 40, acids xlviii are coupled with acylhydrazines using standard coupling conditions, such as EDCI, HOBt, DMF at elevated temperature to afford intermediates lxxxiii (Method V), that are treated with Lawesson's reagent using suitable conditions, for example in toluene under reflux to afford thiadiazoles lxxxiv (Method BA).
Scheme 41-43 describe general procedure for the functional group transformation on Hy.

Scheme 41 above shows a general route for the transformation of 2-fluoropyridyl to 2-substituted aminopyridyl to give the compounds of formula lxxxvi.
As shown in Scheme 41, compounds lxxxv can be treated with amines at elevated temperature or under microwave irradiation to give 2-aminopyridines lxxxvi (Method BB).

Scheme 42 above shows a general route for the transformation of 2-halopyridyl to 2-acylaminopyridyl by Buchwald reaction to give the compounds formula lxxxviii.
As shown in Scheme 42, compounds lxxxvii can be treated with amides or carboxamides in the presence of a suitable catalyst, such as Pd2 dba3, XantPhos, base like cesium carbonate in an appropriate solvent, for example dioxane at elevated temperature or under microwave irradiation to give acylaminopyridines lxxxviii (Method T).

As shown in Scheme 43, compounds lxxxix can be coupled with stannanes under suitable conditions, for example Pd(PPh3)4, CuI, LiCl in dioxane at elevated temperature to give compounds xc (Method K).
Oxidation of thioethers xc to sulfones xci can be achieved using a suitable oxidant, for example mCPBA in DCM (Method BC).
Methanesulfonyl group of sulfones xci can be displaced by treatment with amines in a suitable solvent, for example THF to afford 2-aminopyrimidines xcii (method H).
Schemes 44-52 describe the procedures for the synthesis of building blocks for Hy.

Scheme 44 above shows a general method for the synthesis of imidazo[1,2-a]pyridines xciv. As shown in Scheme 44, 2-aminopyridines xciii are condensed with alfa-halogenated beta-ketoesters in a suitable solvent, for example ethanol at elevated temperature to afford intermediate esters, that are hydrolyzed using standard conditions, such as aqueous sodium hydroxide in THF followed by acidic workup to give acids xciv (Method BD).

Scheme 45 above shows a general method for the synthesis of imidazo[1,2-b]pyridazines xcvi.
As shown in Scheme 45, 2-aminopyridazines xcv are condensed with alfa-halogenated beta-ketoesters in a suitable solvent, for example ethanol at elevated temperature to afford intermediate esters, that are hydrolyzed using standard conditions, such as aqueous sodium hydroxide in THF followed by acidic workup to give acids xcvi (Method BD).

Scheme 46 above shows a general method for the synthesis of imidazo[2,1-b][1,3]thiazoles xcviii.
As shown in Scheme 46, 2-aminothiazoles xcvii are condensed with alfa-halogenated beta-ketoesters in a suitable solvent, for example ethanol at elevated temperature to afford intermediate esters, that are hydrolyzed using standard conditions, such as aqueous sodium hydroxide in THF followed by acidic workup to give acids xcviii (Method BD).

Scheme 47 above shows a general method for the synthesis of pyrazolo[1,5-a]pyridines ci. As shown in Scheme 47, pyridines xcix are N-aminated with a suitable agent, such as 0-(mesitylsulfonyl)hydroxylamine using appropriate conditions, for example toluene or ethyl acetate as solvent (Method BE).
Resulting N-aminopyridinium salts c are then condensed with alkynylcarboxylic acid esters with a suitable base, such as potassium carbonate in a suitable solvent, for example DMF to afford intermediate esters, that are hydrolyzed using standard conditions, such as aqueous sodium hydroxide in THF followed by acidic workup to give acids ci (Method BF).

Scheme 48 above shows a general method for the synthesis of pyrazolo[5,1-b][1,3]thiazoles cv.
As shown in Scheme 48, 2-methylthiazoles cii are N-aminated with a suitable agent, such as O-(mesitylsulfonyl)hydroxylamine using appropriate conditions, for example toluene or ethyl acetate as solvent (Method BE).
Resulting N-aminothiazolium salts ciii are then condensed with acetic anhydride and potassium acetate at elevated temperature to afford methyl ketone intermediate civ (Method BG), which can be converted to carboxylic acid cv moiety by well known functional transformation of methyl keton to carboxylic acid.

Scheme 49 above shows an alternative method for the synthesis of pyrazolopyridines cvii. As shown in Scheme 49, halides lxxxix, which can be prepared by the procedure described in schemes 3, 5, 6 are treated with alkynyl stannanes in the presence of a suitable catalysts, such as Pd(PPh3)4, CuI, with LiCl in an appropriate solvent, like dioxane at elevated temperature to give alkynes of formula cvi (Method BH). Alkynes cvi are then coupled with N-aminopyridinium salts with a base, like potassium carbonate in a suitable solvent, for example DMF to afford compounds of formula cvii (Method BF).

Scheme 50 above shows an alternative method for the synthesis of imidazolopyridines cxi. As shown in Scheme 50, 2-methylthiazoles cviii are deprotonated with a suitable reagent, such as n-BuLi and subsequently treated with Weinreb amides in a suitable solvent, such as THF to give ketones cix (Method BI). Halogenation of ketones is achieved using standard conditions, for example NBS in DCM (Method C) and the resulting haloketones cx are then treated with aminopyridines in a suitable solvent, for example ethanol at elevated temperature to give compounds of formula cxi (Method BD).

Scheme 51 above shows a general method for the synthesis of bicyclic lactam building blocks cxvii and cxviii. As shown in Scheme 51, substituted 2-chloro-4-fluoropyridines can be amidated, for example with BocNH2, Pd2 dba3 and a suitable ligand, such as X-Phos in the presence of a base, for example cesium carbonate in an appropriate solvent, like dioxane to afford Boc-protected 2-aminopyridines cxiii (Method T). Compounds cxiii can be deprotonated, for example using n-BuLi/TMED A in THF at low temperature (Method M) and then quenched with a molecule of halogen, such as iodine in THF (Method N) to give halogenated compounds cxiv. Compounds cxiv can be coupled with diethoxypropene using a suitable Pd catalyst, such as Di-mu-chlorobis[5-hydroxy-2-[1-(hydroxyimino-kappaN)ethyl]phenyl-kappaC]palladium(II) dimer with an appropriate base, like N,N-diisopropylethylamine in a suitable solvent, for example DMF-water mixture (Method BJ) to afford lactams of formula cxv. Transformation of fluoro cxv into hydroxyl analogs cxvi can be carried out using a standard procedure, for example treatment with benzyl alcohol in the presence of a base, such as sodium hydride at elevated temperature and subsequent debenzylation, such as using hydrogenation with Pd/C catalyst in a suitable solvent, such as ethanol (Method BK). Triflates cxvii can be formed by treatment of cxvi with a suitable reagent, for example triflic anhydride using appropriate conditions, such as pyridine as a base in DCM (Method U). Triflates cxvii can be coupled with stannanes xxix, obtained in Scheme 6 using standard Stille conditions (Method K). Alternatively, triflates cxvii can be transformed into stannanes cxviii using a suitable method, such as heating with hexamethyldistannane, Pd(PPh3)4 in a suitable solvent, like THF (Method BL). Stannanes cxviii can be then coupled with thiophene/thiazole halides lxxxix, which can be prepared by the procedures described in schemes 3, 5, 6 using standard Stille conditions (Method K).

Scheme 52 above shows an alternative method for the synthesis of bicyclic lactam building blocks cxxiii. As shown in Scheme 52, compounds cxix can be deprotonated with a suitable reagent, such as n-BuLi in THF at low temperature (Method M) and then treated with DMF to produce carbaldehydes cxx (Method BM). Aldehyde group in cxx can be then treated with enolate generated from t-Butylacetate and LDA in a suitable solvent, such as THF at low temperature (Method BN) to form intermediate β-hydroxyesters cxxi, that can be cyclized to lactams cxxii using an acid, such as HCl in water at elevated temperature (Method BO). Halides cxxii can be coupled with stannanes xxix, obtained in Scheme 6 using standard Stille conditions (Method K). Alternatively, transformation of aryl halides cxxii to stannanes cxxiii can be carried out using hexamethyldistannane, Pd(PPh3)4 in a suitable solvent, like THF (Method BL). Stannanes cxviii can be then coupled with thiophene/thiazole halides lxxxix, which can be prepared by the procedures described in schemes 3, 5, 6 using standard Stille conditions (Method K).
5. Uses, Formulation and Administration
As discussed above, the present invention provides compounds that are useful as inhibitors of PI3K enzymes, and thus the present compounds are useful for treating proliferative, inflammatory, or cardiovascular disorders such as tumor and/or cancerous cell growth mediated by PI3K. In particular, the compounds are useful in the treatment of cancers in a subject, including, but not limited to, lung and bronchus, prostate, breast, pancreas, colon and rectum, thyroid, liver and intrahepatic bile duct, hepatocellular, gastric, glioma/glioblastoma, endometrial, melanoma, kidney, and renal pelvis, urinary bladder, utering corpus, uterine cervix, ovary, multiple myeloma, esophagus, acute myelogenous leukemia, chronic myelogenous leukemia, lymphocytic leukemia, myeloid leukemia, brain, oral cavity, and pharynx, small intestine, non-Hodgkin lymphoma, and villous colon adenoma.
In some embodiments, compounds of the invention are suitable for the treatment of breast cancer, bladder cancer, colon cancer, glioma, glioblastoma, lung cancer, hepatocellular cancer, gastric cancer, melanoma, thyroid cancer, endometrial cancer, renal cancer, cervical cancer, pancreatic cancer, esophageal cancer, prostate cancer, brain cancer, or ovarian cancer.
In other embodiments, compounds of the invention are suitable for the treatment of inflammatory and cardiovascular disorders including, but not limited to, allergies/anaphylaxis, acute and chronic inflammation, rheumatoid arthritis; autoimmunity disorders, thrombosis, hypertension, cardiac hypertrophy, and heart failure.
Accordingly, in another aspect of the present invention, pharmaceutical compositions are provided, wherein these compositions comprise any of the compounds as described herein, and optionally comprise a pharmaceutically acceptable carrier, adjuvant or vehicle. In certain embodiments, these compositions optionally further comprise one or more additional therapeutic agents.
It will also be appreciated that certain of the compounds of present invention can exist in free form for treatment, or where appropriate, as a pharmaceutically acceptable derivative thereof. According to the present invention, a pharmaceutically acceptable derivative includes, but is not limited to, pharmaceutically acceptable prodrugs, salts, esters, salts of such esters, or any other adduct or derivative which upon administration to a patient in need is capable of providing, directly or indirectly, a compound as otherwise described herein, or a metabolite or residue thereof.
As used herein, the term “pharmaceutically acceptable salt” refers to those salts which are, within the scope of sound medical judgement, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response and the like, and are commensurate with a reasonable benefit/risk ratio. A “pharmaceutically acceptable salt” means any non-toxic salt or salt of an ester of a compound of this invention that, upon administration to a recipient, is capable of providing, either directly or indirectly, a compound of this invention or an inhibitorily active metabolite or residue thereof. As used herein, the term “inhibitorily active metabolite or residue thereof” means that a metabolite or residue thereof is also an inhibitor of PI3K.
Pharmaceutically acceptable salts are well known in the art. For example, S. M. Berge et al., describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 1977, 66, 1-19, incorporated herein by reference. Pharmaceutically acceptable salts of the compounds of this invention include those derived from suitable inorganic and organic acids and bases. Examples of pharmaceutically acceptable, nontoxic acid addition salts are salts of an amino group formed with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid or with organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid or malonic acid or by using other methods used in the art such as ion exchange. Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate salts, and the like. Salts derived from appropriate bases include alkali metal, alkaline earth metal, ammonium and N+(C1-4alkyl)4 salts. This invention also envisions the quaternization of any basic nitrogen-containing groups of the compounds disclosed herein. Water or oil-soluble or dispersable products may be obtained by such quaternization. Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like. Further pharmaceutically acceptable salts include, when appropriate, nontoxic ammonium, quaternary ammonium, and amine cations formed using counterions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, loweralkyl sulfonate and aryl sulfonate.
As described above, the pharmaceutically acceptable compositions of the present invention additionally comprise a pharmaceutically acceptable carrier, adjuvant, or vehicle, which, as used herein, includes any and all solvents, diluents, or other liquid vehicle, dispersion or suspension aids, surface active agents, isotonic agents, thickening or emulsifying agents, preservatives, solid binders, lubricants and the like, as suited to the particular dosage form desired. Remington's Pharmaceutical Sciences, Sixteenth Edition, E. W. Martin (Mack Publishing Co., Easton, Pa., 1980) discloses various carriers used in formulating pharmaceutically acceptable compositions and known techniques for the preparation thereof. Except insofar as any conventional carrier medium is incompatible with the compounds of the invention, such as by producing any undesirable biological effect or otherwise interacting in a deleterious manner with any other component(s) of the pharmaceutically acceptable composition, its use is contemplated to be within the scope of this invention. Some examples of materials which can serve as pharmaceutically acceptable carriers include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins, such as human serum albumin, buffer substances such as phosphates, glycine, sorbic acid, or potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes, such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinyl pyrrolidone, polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, wool fat, sugars such as lactose, glucose and sucrose; starches such as corn starch and potato starch; cellulose and its derivatives such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; powdered tragacanth; malt; gelatin; talc; excipients such as cocoa butter and suppository waxes; oils such as peanut oil, cottonseed oil; safflower oil; sesame oil; olive oil; corn oil and soybean oil; glycols; such a propylene glycol or polyethylene glycol; esters such as ethyl oleate and ethyl laurate; agar; buffering agents such as magnesium hydroxide and aluminum hydroxide; alginic acid; pyrogen-free water; isotonic saline; Ringer's solution; ethyl alcohol, and phosphate buffer solutions, as well as other non-toxic compatible lubricants such as sodium lauryl sulfate and magnesium stearate, as well as coloring agents, releasing agents, coating agents, sweetening, flavoring and perfuming agents, preservatives and antioxidants can also be present in the composition, according to the judgment of the formulator.
In yet another aspect, a method for treating a proliferative, inflammatory, or cardiovascular disorder is provided comprising administering an effective amount of a compound, or a pharmaceutical composition to a subject in need thereof. In certain embodiments of the present invention an “effective amount” of the compound or pharmaceutical composition is that amount effective for treating a proliferative, inflammatory, or cardiovascular disorder, or is that amount effective for treating cancer. In other embodiments, an “effective amount” of a compound is an amount which inhibits binding of PI3K and thereby blocks the resulting signaling cascades that lead to the abnormal activity of growth factors, receptor tyrosine kinases, protein serine/threonine kinases, G protein coupled receptors and phospholipid kinases and phosphatases.
The compounds and compositions, according to the method of the present invention, may be administered using any amount and any route of administration effective for treating the disease. The exact amount required will vary from subject to subject, depending on the species, age, and general condition of the subject, the severity of the infection, the particular agent, its mode of administration, and the like. The compounds of the invention are preferably formulated in dosage unit form for ease of administration and uniformity of dosage. The expression “dosage unit form” as used herein refers to a physically discrete unit of agent appropriate for the patient to be treated. It will be understood, however, that the total daily usage of the compounds and compositions of the present invention will be decided by the attending physician within the scope of sound medical judgment. The specific effective dose level for any particular patient or organism will depend upon a variety of factors including the disease being treated and the severity of the disease; the activity of the specific compound employed; the specific composition employed; the age, body weight, general health, sex and diet of the patient; the time of administration, route of administration, and rate of excretion of the specific compound employed; the duration of the treatment; drugs used in combination or coincidental with the specific compound employed, and like factors well known in the medical arts. The term “patient”, as used herein, means an animal, preferably a mammal, and most preferably a human.
The pharmaceutically acceptable compositions of this invention can be administered to humans and other animals orally, rectally, parenterally, intracisternally, intravaginally, intraperitoneally, topically (as by powders, ointments, or drops), bucally, as an oral or nasal spray, or the like, depending on the severity of the infection being treated. In certain embodiments, the compounds of the invention may be administered orally or parenterally at dosage levels of about 0.01 mg/kg to about 50 mg/kg and preferably from about 1 mg/kg to about 25 mg/kg, of subject body weight per day, one or more times a day, to obtain the desired therapeutic effect.
Liquid dosage forms for oral administration include, but are not limited to, pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs. In addition to the active compounds, the liquid dosage forms may contain inert diluents commonly used in the art such as, for example, water or other solvents, solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils (in particular, cottonseed, groundnut, corn, germ, olive, castor, and sesame oils), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof. Besides inert diluents, the oral compositions can also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.
Injectable preparations, for example, sterile injectable aqueous or oleaginous suspensions may be formulated according to the known art using suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation may also be a sterile injectable solution, suspension or emulsion in a nontoxic parenterally acceptable diluent or solvent, for example, as a solution in 1,3-butanediol. Among the acceptable vehicles and solvents that may be employed are water, Ringer's solution, U.S.P. and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose any bland fixed oil can be employed including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid are used in the preparation of injectables.
The injectable formulations can be sterilized, for example, by filtration through a bacterial-retaining filter, or by incorporating sterilizing agents in the form of sterile solid compositions which can be dissolved or dispersed in sterile water or other sterile injectable medium prior to use.
In order to prolong the effect of a compound of the present invention, it is often desirable to slow the absorption of the compound from subcutaneous or intramuscular injection. This may be accomplished by the use of a liquid suspension of crystalline or amorphous material with poor water solubility. The rate of absorption of the compound then depends upon its rate of dissolution that, in turn, may depend upon crystal size and crystalline form. Alternatively, delayed absorption of a parenterally administered compound form is accomplished by dissolving or suspending the compound in an oil vehicle. Injectable depot forms are made by forming microencapsule matrices of the compound in biodegradable polymers such as polylactide-polyglycolide. Depending upon the ratio of compound to polymer and the nature of the particular polymer employed, the rate of compound release can be controlled. Examples of other biodegradable polymers include poly(orthoesters) and poly(anhydrides). Depot injectable formulations are also prepared by entrapping the compound in liposomes or microemulsions that are compatible with body tissues.
Compositions for rectal or vaginal administration are preferably suppositories which can be prepared by mixing the compounds of this invention with suitable non-irritating excipients or carriers such as cocoa butter, polyethylene glycol or a suppository wax which are solid at ambient temperature but liquid at body temperature and therefore melt in the rectum or vaginal cavity and release the active compound.
Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In such solid dosage forms, the active compound is mixed with at least one inert, pharmaceutically acceptable excipient or carrier such as sodium citrate or dicalcium phosphate and/or a) fillers or extenders such as starches, lactose, sucrose, glucose, mannitol, and silicic acid, b) binders such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidinone, sucrose, and acacia, c) humectants such as glycerol, d) disintegrating agents such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate, e) solution retarding agents such as paraffin, f) absorption accelerators such as quaternary ammonium compounds, g) wetting agents such as, for example, cetyl alcohol and glycerol monostearate, h) absorbents such as kaolin and bentonite clay, and i) lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, and mixtures thereof. In the case of capsules, tablets and pills, the dosage form may also comprise buffering agents.
Solid compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polyethylene glycols and the like. The solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings and other coatings well known in the pharmaceutical formulating art. They may optionally contain opacifying agents and can also be of a composition that they release the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract, optionally, in a delayed manner. Examples of embedding compositions that can be used include polymeric substances and waxes. Solid compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polethylene glycols and the like.
The active compounds can also be in micro-encapsulated form with one or more excipients as noted above. The solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings, release controlling coatings and other coatings well known in the pharmaceutical formulating art. In such solid dosage forms the active compound may be admixed with at least one inert diluent such as sucrose, lactose or starch. Such dosage forms may also comprise, as is normal practice, additional substances other than inert diluents, e.g., tableting lubricants and other tableting aids such a magnesium stearate and microcrystalline cellulose. In the case of capsules, tablets and pills, the dosage forms may also comprise buffering agents. They may optionally contain opacifying agents and can also be of a composition that they release the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract, optionally, in a delayed manner. Examples of embedding compositions that can be used include polymeric substances and waxes.
Dosage forms for topical or transdermal administration of a compound of this invention include ointments, pastes, creams, lotions, gels, powders, solutions, sprays, inhalants or patches. The active component is admixed under sterile conditions with a pharmaceutically acceptable carrier and any needed preservatives or buffers as may be required. Ophthalmic formulation, ear drops, and eye drops are also contemplated as being within the scope of this invention. Additionally, the present invention contemplates the use of transdermal patches, which have the added advantage of providing controlled delivery of a compound to the body. Such dosage forms can be made by dissolving or dispensing the compound in the proper medium. Absorption enhancers can also be used to increase the flux of the compound across the skin. The rate can be controlled by either providing a rate controlling membrane or by dispersing the compound in a polymer matrix or gel.
While one or more of the inventive compounds may be used in an application of monotherapy to treat a disorder, disease or symptom, they also may be used in combination therapy, in which the use of an inventive compound or composition (therapeutic agent) is combined with the use of one or more other therapeutic agents for treating the same and/or other types of disorders, symptoms and diseases. Combination therapy includes administration of the therapeutic agents concurrently or sequentially. Alternatively, the therapeutic agents can be combined into one composition which is administered to the patient.
In one embodiment, the compounds of this invention are used in combination with other therapeutic agents, such as other inhibitors of PI3K. In some embodiments, a compound of the invention is administered in conjunction with a therapeutic agent selected from the group consisting of cytotoxic agents, radiotherapy, and immunotherapy. It is understood that other combinations may be undertaken while remaining within the scope of the invention.
Another aspect of the invention relates to inhibiting PI3K, activity in a biological sample or a patient, which method comprises administering to the patient, or contacting said biological sample with a compound of formula I or a composition comprising said compound. The term “biological sample”, as used herein, generally includes in vivo, in vitro, and ex vivo materials, and also includes, without limitation, cell cultures or extracts thereof; biopsied material obtained from a mammal or extracts thereof; and blood, saliva, urine, feces, semen, tears, or other body fluids or extracts thereof.
Still another aspect of this invention is to provide a kit comprising separate containers in a single package, wherein the inventive pharmaceutical compounds, compositions and/or salts thereof are used in combination with pharmaceutically acceptable carriers to treat disorders, symptoms and diseases where PI3K kinase plays a role.
TABLE 1Table 1 below depicts certain compounds represented bycompounds of general formula I-A and I-B.                                                                                                                                                                                                                                                                                                                                                  